Neuroactive 19-alkoxy-17-substituted steroids, prodrugs thereof, and methods of treatment using same

ABSTRACT

The present disclosure is generally directed to neuroactive 19-alkoxy-17-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority benefit of U.S. Provisional PatentApplication Ser. No. 61/738,822, filed on Dec. 18, 2012, the entirecontent of which is incorporated herein by reference.

GOVERNMENT SUPPORT

The claimed subject matter was developed with Government support underNIH Grant #GM47969, awarded by the National Institute of Health.Accordingly, the Government has certain rights in the claimed subjectmatter.

BACKGROUND OF THE DISCLOSURE

The present disclosure is generally directed to novel compounds havingutility as an anesthetic and/or in the treatment of disorders relatingto GABA function and activity. More specifically, the present disclosureis directed to steroids having a 19-alkoxy-17-substituted tetracyclicstructure that are neuroactive and suitable for use as an anesthetic, aswell as pharmaceutically acceptable salts and prodrugs thereof, andpharmaceutical compositions containing them.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitterof the central nervous system. GABA activates two types of receptors,the inotropic GABA_(A) and the metabotropic GABA_(B) receptor.Activation of the GABA_(B) receptor by GABA causes hyperpolarization anda resultant inhibition of neurotransmitter release. The GABA_(A)receptor subtype regulates neuronal excitability and rapid mood changes,such as anxiety, panic, and stress response. GABA_(A) receptors arechloride ion channels; as a result, activation of the receptor inducesincreased inward chloride ion flux, resulting in membranehyperpolarization and neuronal inhibition. Drugs that stimulate GABA_(A)receptors, such as benzodiazepines and barbiturates, have anticonvulsiveeffects (by reducing neuronal excitability and raising the seizurethreshold), as well as anxiolytic and anesthetic effects.

The effect of certain steroids on GABA_(A) receptors has beenwell-established. As a result, researchers continue to pursue thediscovery and synthesis of neuroactive steroids that may act asanesthetics and/or that may serve to provide treatment for disordersrelated to GABA function. For example, it is now widely accepted thatthe intravenous anesthetic alphaxalone (Compound A, below) causesgeneral anesthesia in humans because it allosterically increaseschloride currents mediated by GABA acting at GABA_(A) receptors in thebrain. However, the various structural features that enable thiscompound to function in the way it does have, to-date, not been fullyunderstood. For example, in contrast to alphaxalone, Δ¹⁶-alphaxalone(Compound B, below), has been observed to have greatly diminishedallosteric activity at GABA_(A) receptors and is not used as anintravenous general anesthetic in humans.

The difference in performance of these two compounds, which some haveattributed to the presence of the carbon-carbon double bond in theD-ring, has attracted the attention of many researchers. In fact,recently, it was determined that the effect this double bond has onanesthetic activity may depend on the group attached at C-17 on theD-ring. (See Bandyopadhyaya, A. K., et al., “Neurosteroid analogues. 15.A comparative study of the anesthetic and GABAergic actions ofalphaxalone, Δ¹⁶-alphaxalone and their corresponding 17-carbonitrileanalogues. Bioorg. Med. Chem. Lett., 20: 6680-4 (2010).)

In addition to anesthetic properties, neuroactive steroids may be usedto treat disorders related to GABA function. For example, neuroactivesteroids, such as progesterone, may be used as sedative-hypnotics,exhibiting benzodiazepine-like actions, inducing reduced sleep latencyand increased non-REM sleep with only small changes in slow wave and REMsleep. Further, drugs that enhance GABA responses are often used totreat anxiety in humans. Thus, it might be expected thatGABA-potentiating steroids would exhibit anxiolytic effects. Neuroactivesteroids may also be used to treat depression, given that accumulatingevidence suggests that patients with major depression have decreasedlevels of GABAergic neurosteroids and that certain treatments fordepression alter levels of these steroids. Although GABA is nottypically thought to play a critical role in the biology of depression,there is evidence that low GABAergic activity may predispose one to mooddisorders. Finally, inhibition of NMDA receptors and enhancement ofGABA_(A) receptors appear to play important roles in mediating the acuteeffects of ethanol in the nervous system, while related studies suggestthat GABAergic neurosteroids may be involved in some of thepharmacological effects of ethanol and that neuroactive steroids may beuseful in treating ethanol withdrawal.

In view of the foregoing, it is clear that there are a number ofpotentially advantageous uses for neurosteroids. As a result, there is acontinuing need for the further synthesis and understanding of newneuroactive steroids, particularly those having utility as an anestheticand/or in the treatment of a disorder relating to GABA function andactivity.

SUMMARY OF THE DISCLOSURE

In one aspect, the present disclosure is directed to a compound having astructure of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

R₁ is selected from (C₁-C₄ alkyl)-O, spirooxirane, cyano, ═O, nitro,(C₁-C₄ alkyl)C(O), and HO(C₁-C₄ alkyl)C(O), with R₁ preferably being inthe beta position when other than ═O, and/or in one or more preferredembodiments C₁-C₄ alkyl being methyl, R₁ therefore being is selectedfrom methoxy, spirooxirane, cyano, ═O, nitro, CH₃C(O)— and OHCH₂C(O)—;

R₂ is ═O, H, or OR_(a), where R_(a) is selected from H, optionallysubstituted C₁-C₄ alkyl, or optionally substituted aryl, with theproviso that when R₂ is ═O, R₈ is not present;

R₃ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, or optionallysubstituted aryl;

R₄ is independently selected from H and unsubstituted C₁-C₄ alkyl;

R₅ is substituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, oroptionally substituted C₂-C₄ alkynyl (and in particular isalkoxy-substituted methyl, or even more particular is —CH₂—OR_(b), whereR_(b) is C₁-C₄ alkyl, or even still more particularly is —CH₂—OCH₃);

R₆ is H, optionally substituted C₁-C₄ alkyl, or optionally substitutedC₁-C₄ alkoxy;

R₇ is H, optionally substituted C₁-C₄ alkoxy, or an optionallysubstituted morpholinyl ring;

R₈, when present, is H or optionally substituted C₁-C₄ alkyl;

- - - denotes an optional, additional C—C bond, resulting in either aC═C bond between C₄-C₅ or C₅-C₆, with the proviso that when present, theR₅—H substituent is not present; and,

- - - denotes an optional, additional C—C bond, resulting in a C═C bondbetween C₁₆-C₁₇, with the proviso that when present, the R₁ is not ═O.

The present disclosure is further directed to a pharmaceuticallyacceptable salt of the noted compounds, or alternatively to prodrugsthereof. In one particular embodiment, the present disclosure isdirected to a compound having a structure of Formula (II):

or a pharmaceutically acceptable salt thereof;

wherein:

R₁ is selected from (C₁-C₄ alkyl)-O, spirooxirane, cyano, ═O, nitro,(C₁-C₄ alkyl)C(O), and HO(C₁-C₄ alkyl)C(O), with R₁ preferably being inthe beta position when other than ═O, and/or in one or more preferredembodiments C₁-C₄ alkyl being methyl, R₁ therefore being is selectedfrom methoxy, spirooxirane, cyano, ═O, nitro, CH₃C(O)— and OHCH₂C(O)—;

R₂ is ═O, H, or OR_(a), where R_(a) is selected from H, optionallysubstituted C₁-C₄ alkyl, or optionally substituted aryl, with theproviso that when R₂ is ═O, R₈ is not present;

R_(x) is ═O or OR_(d), where R_(d) is H or C(O)R_(e), where R_(e) isoptionally substituted C₁-C₂₂ alkyl or optionally substituted C₂-C₂₂alkenyl, with the proviso that when R_(x) is OH, it is in the betaconfiguration;

R₄ is independently selected from H and unsubstituted C₁-C₄ alkyl;

R₅ is substituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, oroptionally substituted C₂-C₄ alkynyl (and in particular isalkoxy-substituted methyl, or even more particular is —CH₂—OR_(b), whereR_(b) is C₁-C₄ alkyl, or even still more particularly is —CH₂—OCH₃);

R₆ is H, optionally substituted C₁-C₄ alkyl, or optionally substitutedC₁-C₄ alkoxy;

R₇ is H, optionally substituted C₁-C₄ alkoxy, or an optionallysubstituted morpholinyl ring;

R₈, when present, is H or optionally substituted C₁-C₄ alkyl;

- - - denotes an optional, additional C—C bond, resulting in either aC═C bond between C₄-C₅ or C₅-C₆, with the proviso that when present, theC₅—H substituent is not present; and,

- - - denotes an optional, additional C—C bond, resulting in a C═C bondbetween C₁₆-C₁₇, with the proviso that when present, the R₁ is not ═O,

provided that the compound does not have one of the followingstructures:

or alternatively provided that: (i) when R_(x) is ═O, a C═C bond ispresent between C₄-C₅, and R₅ is CH₂OCH₃, then R₁ is selected frommethoxy, spirooxirane, cyano, nitro, and CH₃C(O)—; and/or (ii) whenR_(x) is beta-OH, a C═C bond is present between C₅-C₆, and R₅ isCH₂OCH₃, then R₁ is selected from methoxy, spirooxirane, cyano, nitro,and HOCH₂C(O)—.

The present disclosure is still further directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of one or moreof the above-noted steroids, or prodrugs, or pharmaceutically acceptablesalts thereof, and optionally a pharmaceutically acceptable carrier. Thepresent disclosure also provides kits comprising steroids, saltsthereof, pro-drugs thereof, and/or pharmaceutical compositions thereof.

The present disclosure further provides methods of inducing anesthesiain a subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of one or more of theabove-noted steroids, or prodrugs, or pharmaceutically acceptable saltsthereof, or a pharmaceutical composition thereof.

The present disclosure further provides methods of treating disordersrelated to GABA function in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of one or more of the above-noted steroids, or prodrugs, orpharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof. In certain embodiments, the disorder is selectedfrom the group consisting of insomnia, mood disorders, convulsivedisorders, anxiety, or symptoms of ethanol withdrawal.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

In accordance with the present disclosure, it has been discovered thatcompounds having certain 17-substituted steroid structures, morespecifically certain 19-alkoxy-17-substituted steroid structures, andeven more specifically certain 19-methoxy-17-substituted steroidstructures, are neuroactive and are also suitable for use as anestheticsand in the treatment of disorders associated with GABA function, as wellas pharmaceutically acceptable salts and prodrugs thereof. The compoundsmay be used, for example, as an effective continuous infusion sedativefor non-surgical procedures (e.g., colonoscopy). The compounds alsooffer advantages over anesthetics known in the art, such as a lowerlikelihood for bacterial contamination, as well as an improvedrelationship with solubilizing agents.

1. Steroid Structure

Generally speaking, the steroid of the present disclosure has atetracyclic, fused ring structure, such as a cyclopenta[a]phenanthrenering system (an embodiment of which is illustrated and discussed ingreater detail below), wherein the C₃-position of the A ring has ahydroxyl substituent in the α-position, and the C₁₇-position of the Dring has a substituent attached thereto selected from the groupconsisting of methoxy, spirooxirane, cyano, ═O, nitro, CH₃C(O)—, andHOCH₂C(O)— (with R₁ preferably being in the beta position when otherthan ═O).

More particularly, however, the present disclosure is directed, incertain embodiments, to a steroid having the structure of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

R₁ is selected from (C₁-C₄ alkyl)-O (e.g., methoxy, ethoxy, propoxy,butoxy), spirooxirane, cyano, ═O, nitro, (C₁-C₄ alkyl)C(O) (e.g.,CH₃C(O), CH₃CH₂C(O), CH₃CH₂CH₂C(O), CH₃CH₂CH₂CH₂C(O)), and HO(C₁-C₄alkyl)C(O) (e.g., HOCH₂C(O), HOCH₂CH₂C(O), HOCH₂CH₂CH₂C(O),HOCH₂CH₂CH₂CH₂C(O)), with R₁ preferably being in the beta position whenother than ═O, and/or in one or more preferred embodiments C₁-C₄ alkylbeing methyl, R₁ therefore being is selected from methoxy, spirooxirane,cyano, ═O, nitro, CH₃C(O)— and OHCH₂C(O)—;

R₂ is ═O, H, or OR_(a), where R_(a) is selected from H, optionallysubstituted C₁-C₄ alkyl, or optionally substituted aryl, with theproviso that when R₂ is ═O, R₈ is not present;

R₃ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, or optionallysubstituted aryl;

R₄ is independently selected from H and unsubstituted C₁-C₄ alkyl;

R₅ is substituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, oroptionally substituted C₂-C₄ alkynyl (and in particular isalkoxy-substituted methyl, or even more particular is —CH₂—OR_(b), whereR_(b) is C₁-C₄ alkyl, or even still more particularly is —CH₂—OCH₃);

R₆ is H, optionally substituted C₁-C₄ alkyl, or optionally substitutedC₁-C₄ alkoxy;

R₇ is H, optionally substituted C₁-C₄ alkoxy, or an optionallysubstituted morpholinyl ring;

R₈, when present, is H or optionally substituted C₁-C₄ alkyl;

- - - denotes an optional, additional C—C bond, resulting in either aC═C bond between C₄-C₅ or C₅-C₆, with the proviso that when present, theR₅—H substituent is not present; and,

- - - denotes an optional, additional C—C bond, resulting in a C═C bondbetween C₁₆-C₁₇, with the proviso that when present, the R₁ is not ═O.

As generally defined above, R₁ is selected from (C₁-C₄ alkyl)-O,spirooxirane, cyano, ═O, nitro, (C₁-C₄ alkyl)C(O), and HO(C₁-C₄alkyl)C(O). In certain embodiments, R₁ is preferably in the betaposition (when other than ═O, or when a C═C is not present betweenC₁₆-C₁₇). In certain embodiments, R₁ is selected from (C₁-C₄ alkyl)-O(e.g., methoxy, ethoxy, propoxy, butoxy), spirooxirane, cyano, ═O,nitro, (C₁-C₄ alkyl)C(O) (e.g., CH₃C(O), CH₃CH₂C(O), CH₃CH₂CH₂C(O),CH₃CH₂CH₂CH₂C(O)), and HO(C₁-C₄ alkyl)C(O) (e.g., HOCH₂C(O),HOCH₂CH₂C(O), HOCH₂CH₂CH₂C(O), HOCH₂CH₂CH₂CH₂C(O)). In certainembodiments, C₁-C₄ alkyl is methyl, R₁ therefore being is selected frommethoxy, spirooxirane, cyano, ═O, nitro, CH₃C(O)— and OHCH₂C(O)—.

As generally defined above, R₂ is ═O, H, or OR_(a), where R_(a) isselected from H, optionally substituted C₁-C₄ alkyl, or optionallysubstituted aryl, with the proviso that when R₂ is ═O, R₈ is notpresent. In certain embodiments, R₂ is ═O and R₈ is not present. Incertain embodiments, R₂ is H. In certain embodiments, R₂ is OR_(a). Incertain embodiments, R₂ is OR_(a) and R_(a) is optionally substitutedC₁, C₂, C₃, or C₄ alkyl (e.g., methyl, ethyl), optionally substitutedbenzyl, or C₁, C₂, C₃, or C₄ alkyl substituted with O-aryl, such asO-benzyl. In certain embodiments, R₂ is OR_(a) and R_(a) is optionallysubstituted aryl. In certain embodiments, R₂ is OR_(a) and R_(a) is H.

As generally defined above, R₃ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, or optionally substituted aryl. In certain embodiments, R₃ isH. In certain embodiments, R₃ is optionally substituted C₁, C₂, C₃ or C₄alkyl (e.g., methyl, ethyl, trifluoromethyl, difluoromethyl). In certainembodiments, R₃ is methyl. In certain embodiments, R₃ istrifluoromethyl. In certain embodiments, R₃ is optionally substitutedC₂, C₃ or C₄ alkenyl (e.g., optionally substituted allyl). In certainembodiments, R₃ is optionally substituted C₂, C₃, or C₄ alkynyl (e.g.,optionally substituted acetylene or optionally substituted propargyl).In certain embodiments, R₃ is optionally substituted aryl (e.g.,optionally substituted phenyl, such as phenyl substituted with OH,methyl, or COR_(c), where R_(c) is optionally substituted C₁-C₂₂ alkylor optionally substituted C₂-C₂₂ alkenyl, including for exampleoptionally substituted C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, or C₂₂ alkyl or C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈,C₁₉, C₂₀, C₂₁, or C₂₂ alkenyl).

As generally defined above, R₄ is H or unsubstituted C₁-C₄ alkyl. Incertain embodiments, R₄ is H. In certain embodiments, R₄ isunsubstituted C₁, C₂, C₃ or C₄ alkyl (e.g., methyl, ethyl, n-propyl,isopropyl, or n-butyl).

As generally defined above, R₅ is substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl. Incertain embodiments, R₅ is substituted C₁-C₄ alkyl, and in particular isalkoxy-substituted C₁-C₄ alkyl. In other particular embodiments, R₅ issubstituted methyl, and more particularly is alkoxy-substituted methyl(or even more particularly is —CH₂—OR_(b), where R_(b) is C₁-C₄ alkyl,or even still more particularly is —CH₂—OCH₃). In other embodiments, R₅is optionally substituted C₂-C₄ alkenyl. In other embodiments, R₅ isoptionally substituted C₂-C₄ alkynyl.

As generally defined above, R₆ is H, optionally substituted C₁-C₄ alkyl,or optionally substituted C₁-C₄ alkoxy. In certain embodiments, R₆ is H.In certain embodiments, R₆ is optionally substituted C₁, C₂, C₃, or C₄alkyl (e.g., methyl). In certain embodiments, R₆ is optionallysubstituted C₁, C₂, C₃ or C₄ alkoxy (e.g., methoxy, ethoxy, n-propyloxy,isopropyloxy, or n-butoxy). In certain embodiments, when R₆ is anon-hydrogen group, R₆ is in the alpha (down) position. In certainpreferred embodiments, however, when R₆ is a non-hydrogen group, R₆ isin the beta (up) position.

As generally defined above, R₇ is H, optionally substituted C₁-C₄alkoxy, or an optionally substituted morpholinyl ring. In certainembodiments, R₇ is H. In certain embodiments, R₇ is optionallysubstituted C₁, C₂, C₃ or C₄ alkoxy (e.g., methoxy, ethoxy, n-propyloxy,isopropyloxy, or n-butoxy). In certain embodiments, R₇ is an optionallysubstituted morpholinyl ring. In certain embodiments, when R₇ is anon-hydrogen group, R₇ is in the alpha (down) position. In certainpreferred embodiments, however, when R₇ is a non-hydrogen group, R₇ isin the beta (up) position.

As generally defined above, R₈, when present, is H or optionallysubstituted C₁-C₄ alkyl. In certain embodiments, R₈ is H. In certainembodiments, R₈ is C₁, C₂, C₃ or C₄ optionally substituted alkyl (e.g.,methyl). In certain embodiments, when R₈ is optionally substituted C₁-C₄alkyl, R₈ is in the alpha (down) position. In certain embodiments, whenR₈ is optionally substituted C₁-C₄ alkyl, R₈ is in the beta (up)position.

In certain embodiments, R₂ and R₈ are both H. In certain embodiments, R₂is OR_(a) and R₈ is H.

As generally defined above, - - - denotes an optional, additional C—Cbond, resulting in either a C═C bond between C₄-C₅ or C₅-C₆, with theproviso that when present, the C₅—H substituent is not present. Incertain embodiments, the additional C—C bond is absent, and the hydrogenat C₅ is in the alpha or beta position. In certain embodiments, theadditional C—C bond is absent, and the hydrogen at C₅ is in the alpha(down) position. In certain embodiments, the additional C—C bond isabsent, and the hydrogen at C₅ is in the beta (up) position. In certainembodiments, - - - denotes an additional C—C bond, resulting in a C═Cbond between C₄-C₅. In certain embodiments, - - - denotes an additionalC—C bond, resulting in a C═C bond between C₅-C₆.

As generally defined above, - - - denotes an optional, additional C—Cbond, resulting in a C═C bond, between C₁₆-C₁₇, with the proviso thatwhen present, the R₁ is other than ═O. In certain embodiments, theadditional C—C bond is absent (i.e., there is not C═C bond), andtherefore R₁ may be in the alpha or beta position. In certainembodiments, the additional C—C bond is absent, and the R₁ is in thealpha (down) position. In certain embodiments, the additional C—C bondis absent, and the R₁ is in the beta (up) position.

It is to be noted that the present disclosure contemplates and isintended to encompass all of the various combinations and permutations(i.e., combinations of substituent options, locations and stereochemicalconfigurations) possible here.

For example, in various embodiments, compounds of the present disclosuremay be selected from among those encompassed by the structure of Formula(I), wherein R₂ is ═O; alternatively, R₂ may be H and R₈ is H (e.g., C₁₁thus having two hydrogen atoms bound thereto as substituents). Incertain embodiments, R₂ may be OR_(a), wherein R_(a) is methyl,optionally substituted benzyl, or C₁-C₄ alkyl substituted with O-aryl,such as O-benzyl. In certain embodiments, R₃ may be H, methyl,trifluoromethyl, or substituted aryl (e.g., substituted phenyl, which inturn may be optionally substituted such as, for example, with OH,methyl, or COR_(c), where R_(c)═C₁-C₄ alkyl); further, when R₃ issomething other than H, R₃ is preferably in the β-position. In certainembodiments, each of R₄ and R₆ are independently selected from H andmethyl, R₅ being in the β-configuration and R₆ optionally being in theα-configuration or β-configuration (e.g., when R₆ is methyl), which theβ-configuration being preferred. In certain embodiments, R₇ is selectedfrom H, methoxy, ethoxy, and an optionally substituted morpholinyl ring;further, when R₇ is something other than H, R₇ is preferably in theβ-position. In certain embodiments, R₈, when present, is selected from Hor optionally substituted C₁-C₄ alkyl. In certain embodiments, R₈ ismethyl (e.g., methyl in the alpha-configuration).

In certain embodiments, the C₅—H is in the alpha configuration and theR₅ is, for example, a substituted methyl group (e.g., alkoxy-substitutedmethyl, or in particular a methoxy-substituted methyl) in the betaconfiguration. In certain embodiments, the C5-H is in the betaconfiguration and R₅ is, for example, a substituted methyl (e.g., amethoxy-substituted methyl) group in the beta configuration. In certainembodiments, R₆ is H. In certain embodiments, R₄ is methyl. In certainembodiments, R₂ is ═O or methoxy.

Accordingly, as noted, the steroid of Formula (I) may encompass a numberof various structures in accordance with the present disclosure.

In certain embodiments, wherein R₁ is as defined above, R₃ is in thebeta position, R₄ is methyl, R₅ is substituted methyl in the betaposition, and R₆ is H, provided is a compound of Formula (I-a):

or a pharmaceutically acceptable salt thereof, wherein - - - , R₂, R₃,R₇ and R₈ are as defined herein, and further wherein R_(b) is optionallysubstituted C₁-C₄ alkyl. In certain embodiments, each instance of - - -between C₅-C₆ and C₆-C₇ is absent and C₅—H is in the alpha position. Incertain embodiments, each instance of - - - between C₅-C₆ and C₆-C₇ isabsent and C₅—H is in the beta position. In certain embodiments, eachinstance of - - - between C₁₆-C₁₇ is absent and R₁ is in the betaposition.

In certain embodiments of Formula (I), wherein R₂ is ═O and R₈ isabsent, provided is a compound of Formula (I-b):

or a pharmaceutically acceptable salt thereof, wherein - - - , R₃ and R₇are as defined herein, and further wherein R_(b) is optionallysubstituted C₁-C₄ alkyl. In certain embodiments, each instance of - - -between C₅-C₆ and C₆-C₇ is absent and C₅—H is in the alpha position. Incertain embodiments, each instance of - - - between C₅-C₆ and C₆-C₇ isabsent and C₅—H is in the beta position. In certain embodiments, eachinstance of - - - between C₁₆-C₁₇ is absent and R₁ is in the betaposition.

In certain embodiments of Formula (I), wherein R₂ and R₈ are H, providedis a compound of Formula (I-c):

or a pharmaceutically acceptable salt thereof, wherein - - - , R₂, R₃,and R₇ are as defined herein, and further wherein R_(b) is optionallysubstituted C₁-C₄ alkyl. In certain embodiments, each instance of - - -between C₅-C₆ and C₆-C₇ is absent and C₅—H is in the alpha position. Incertain embodiments, each instance of - - - between C₅-C₆ and C₆-C₇ isabsent and C₅—H is in the beta position. In certain embodiments, eachinstance of - - - between C₁₆-C₁₇ is absent and R₁ is in the betaposition.

In certain embodiments of Formula (I), wherein R₂ is OR_(a) and R₈ is H,provided is a compound of Formula (I-d):

or a pharmaceutically acceptable salt thereof, wherein - - - , R₃, R₇,and R_(a) are as defined herein, and further wherein R_(b) is optionallysubstituted C₁-C₄ alkyl. In certain embodiments, each instance of - - -between C₅-C₆ and C₆-C₇ is absent and C₅—H is in the alpha position. Incertain embodiments, each instance of - - - between C₅-C₆ and C₆-C₇ isabsent and C₅—H is in the beta position. In certain embodiments, eachinstance of - - - between C₁₆-C₁₇ is absent and R₁ is in the betaposition.

In certain embodiments of Formula (I), wherein R₇ is H, provided is acompound of Formula (I-e):

or a pharmaceutically acceptable salt thereof, wherein - - - , R₂, R₃,and R₈ are as defined herein, and further wherein R_(b) is optionallysubstituted C₁-C₄ alkyl. In certain embodiments, each instance of - - -between C₅-C₆ and C₆-C₇ is absent and C₅—H is in the alpha position. Incertain embodiments, each instance of - - - between C₅-C₆ and C₆-C₇ isabsent and C₅—H is in the beta position. In certain embodiments, eachinstance of - - - between C₁₆-C₁₇ is absent and R₁ is in the betaposition.

In certain embodiments of Formula (I), wherein each instance of - - - isabsent and C₅—H is in the alpha position, provided is a compound ofFormula (I-f):

or a pharmaceutically acceptable salt thereof, wherein R₂, R₃, R₇ and R₈are as defined herein, and further wherein R_(b) is optionallysubstituted C₁-C₄ alkyl. In certain embodiments, each instance of - - -between C₁₆-C₁₇ is absent and R₁ is in the beta position.

In certain embodiments of Formula (I), wherein R₇ is H, provided is acompound of Formula (I-g):

or a pharmaceutically acceptable salt thereof, wherein R₂, R₃, and R₈are as defined herein, and further wherein R_(b) is optionallysubstituted C₁-C₄ alkyl. In certain embodiments, each instance of - - -between C₁₆-C₁₇ is absent and R₁ is in the beta position.

In certain embodiments of Formula (I), wherein R₂ is ═O, provided is acompound of Formula (I-h):

or a pharmaceutically acceptable salt thereof, wherein R₃ and R₇ are asdefined herein, and further wherein R_(b) is optionally substitutedC₁-C₄ alkyl. In certain embodiments, each instance of - - - betweenC₁₆-C₁₇ is absent and R₁ is in the beta position.

In certain embodiments of Formula (I), wherein R₂ is OR_(a), provided isa compound of Formula (I-i):

or a pharmaceutically acceptable salt thereof, wherein R_(a), R₃, and R₇are as defined herein, and further wherein R_(b) is optionallysubstituted C₁-C₄ alkyl. In certain embodiments, each instance of - - -between C₁₆-C₁₇ is absent and R₁ is in the beta position.

In certain embodiments of Formula (I), wherein - - - represents anadditional C—C bond, resulting in a C═C bond between C₄-C₅ provided is acompound of Formula (I-j):

or a pharmaceutically acceptable salt thereof, wherein R₃, R₂, R₇ and R₈are as defined herein, and further wherein R_(b) is optionallysubstituted C₁-C₄ alkyl. In certain embodiments, each instance of - - -between C₁₆-C₁₇ is absent and R₁ is in the beta position.

In certain embodiments of Formula (I), wherein - - - represents anadditional C—C bond, resulting in a C═C bond between C₅-C₆ provided is acompound of Formula (I-k):

or a pharmaceutically acceptable salt thereof, wherein R₃, R₂, R₇ and R₈are as defined herein, and further wherein R_(b) is optionallysubstituted C₁-C₄ alkyl. In certain embodiments, each instance of - - -between C₁₆-C₁₇ is absent and R₁ is in the beta position.

It is to be noted that, in one or more of the preferred embodimentsdetailed above, R₁ may, in particular, be selected from methoxy (or moregenerally lower alkoxy, e.g., —O—(C₁-C₄)), or alternatively selectedfrom CH₃C(O)— or HOCH₂C(O)— (or more generally substituted orunsubstituted lower alkyl-carbonyl, e.g., (C₁-C₄)C(O)—, wherein one ormore of the carbon atoms is optionally substituted, such as for exampleby a hydroxyl group). Alternatively, R₁ may be selected from nitro orcyano, with an optional C═C being present between C₁₆-C₁₇. In yetanother alternative embodiment, C₁₇ may be a carbonyl carbon (i.e., R₁is ═O), or it may be part of an oxirane ring fused with the D-ring(i.e., R₁ being a spirooxirane substituent, wherein C₁₇ is the carbonatom common to both rings).

Exemplary compounds of Formula (I) include, but are not limited to, thefollowing:

and pharmaceutically acceptable salts thereof, wherein in one preferredembodiment R_(b) is CH₃.

In certain embodiments, the steroid of Formula (I) is selected from thegroup consisting of:

and pharmaceutically acceptable salts thereof, wherein R₃ is as definedabove, and in one particular embodiment is H, and further wherein inthis or another preferred embodiment R_(b) is CH₃.

In certain embodiments, the steroid of Formula (I) is selected from thegroup consisting of:

and pharmaceutically acceptable salts thereof, wherein R₃ is as definedabove, and in one particular embodiment is H, and further wherein inthis or another preferred embodiment R_(b) is CH₃.

In certain embodiments, the steroid of Formula (I) is selected from thegroup consisting of:

and a pharmaceutically acceptable salt thereof, wherein R₃ and/or R₁ areas defined above, and in one particular embodiment R₃ is H and R₁ ismethoxy, and further wherein in these or other preferred embodimentsR_(b) is CH₃.

In certain embodiments, the steroid of Formula (I) is selected from thegroup consisting of:

and a pharmaceutically acceptable salt thereof, wherein R₃ is as definedabove, and in one particular embodiment is H, and further wherein inthis or another preferred embodiment R_(b) is CH₃.

In certain embodiments, the steroid of Formula (I) is selected from thegroup consisting of:

and a pharmaceutically acceptable salt thereof, wherein R₃ is as definedabove, and in one particular embodiment is H, and further wherein inthis or another preferred embodiment R_(b) is CH₃.

In this regard it is to be noted that the structures provided above areof various exemplary embodiments. As such, they should not be viewed ina limiting sense.

2. Prodrug Structure

In another particular embodiment, the present disclosure is in generaldirected to prodrugs of the various steroids detailed above. Generallyspeaking, as used herein, a “prodrug” refers to an inactive, orsignificantly less active, form of the steroids detailed above (and inparticular the steroids of Formula (I)), which after administration ismetabolized in vivo into one or more active metabolites of the steroidof Formula (I). The prodrug may be formed using means generally known inthe art, and therefore may take essentially any form that would berecognized to one of ordinary skill in the art. The prodrugs of thepresent disclosure may advantageously provide improved absorption,distribution, metabolism and/or excretion optimization, as well asimproved oral bioavailability of the steroids detailed above (and inparticular the steroids of Formula (I)).

In another particular embodiment of the present disclosure the prodrugof a steroid disclosed herein has a structure of Formula (II):

or a pharmaceutically acceptable salt thereof;

wherein:

R₁ is selected from (C₁-C₄ alkyl)-O (e.g., methoxy, ethoxy, propoxy,butoxy), spirooxirane, cyano, ═O, nitro, (C₁-C₄ alkyl)C(O) (e.g.,CH₃C(O), CH₃CH₂C(O), CH₃CH₂CH₂C(O), CH₃CH₂CH₂CH₂C(O)), and HO(C₁-C₄alkyl)C(O) (e.g., HOCH₂C(O), HOCH₂CH₂C(O), HOCH₂CH₂CH₂C(O),HOCH₂CH₂CH₂CH₂C(O)), with R₁ preferably being in the beta position whenother than ═O, and/or in one or more preferred embodiments C₁-C₄ alkylbeing methyl, R₁ therefore being is selected from methoxy, spirooxirane,cyano, ═O, nitro, CH₃C(O)— and OHCH₂C(O)—;

R₂ is ═O, H, or OR_(a), where R_(a) is selected from H, optionallysubstituted C₁-C₄ alkyl, or optionally substituted aryl, with theproviso that when R₂ is ═O, R₈ is not present;

R_(x) is ═O or OR_(d), where R_(d) is H or C(O)R_(e), where R_(e) isoptionally substituted C₁-C₂₂ alkyl or optionally substituted C₂-C₂₂alkenyl, with the proviso that when R_(x) is OH, it is in the betaconfiguration;

R₄ is independently selected from H and unsubstituted C₁-C₄ alkyl;

R₅ is substituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, oroptionally substituted C₂-C₄ alkynyl (and in particular isalkoxy-substituted methyl, or even more particular is —CH₂—OR_(b), whereR_(b) is C₁-C₄ alkyl, or even still more particularly is —CH₂—OCH₃);

R₆ is H, optionally substituted C₁-C₄ alkyl, or optionally substitutedC₁-C₄ alkoxy;

R₇ is H, optionally substituted C₁-C₄ alkoxy, or an optionallysubstituted morpholinyl ring;

R₈, when present, is H or optionally substituted C₁-C₄ alkyl;

- - - denotes an optional, additional C—C bond, resulting in either aC═C bond between C₄-C₅ or C₅-C₆, with the proviso that when present, theC₅—H substituent is not present; and,

- - - denotes an optional, additional C—C bond, resulting in a C═C bondbetween C₁₆-C₁₇, with the proviso that when present, the R₁ is not ═O,

provided that the compound does not have one of the followingstructures:

or alternatively provided that: (i) when R_(x) is ═O, a C═C bond ispresent between C₄-C₅, and R₅ is CH₂OCH₃, then R₁ is selected frommethoxy, spirooxirane, cyano, nitro, and CH₃C(O)—; and/or (ii) whenR_(x) is beta-OH, a C═C bond is present between C₅-C₆, and R₅ isCH₂OCH₃, then R₁ is selected from methoxy, spirooxirane, cyano, nitro,and HOCH₂C(O)—.

In this regard, it is to be noted that the present disclosurecontemplates and is intended to encompass all of the variouscombinations and permutations (i.e., combinations of substituentoptions, locations and stereochemical configurations) possible here.

As generally defined above, R₁ is selected from (C₁-C₄ alkyl)-O,spirooxirane, cyano, ═O, nitro, (C₁-C₄ alkyl)C(O), and HO(C₁-C₄alkyl)C(O). In certain embodiments, R₁ is preferably in the betaposition (when other than ═O, or when a C═C is not present betweenC₁₆-C₁₇). In certain embodiments, R₁ is selected from (C₁-C₄ alkyl)-O(e.g., methoxy, ethoxy, propoxy, butoxy), spirooxirane, cyano, ═O,nitro, (C₁-C₄ alkyl)C(O) (e.g., CH₃C(O), CH₃CH₂C(O), CH₃CH₂CH₂C(O),CH₃CH₂CH₂CH₂C(O)), and HO(C₁-C₄ alkyl)C(O) (e.g., HOCH₂C(O),HOCH₂CH₂C(O), HOCH₂CH₂CH₂C(O), HOCH₂CH₂CH₂CH₂C(O)). In certainembodiments, C₁-C₄ alkyl is methyl, R₁ therefore being is selected frommethoxy, spirooxirane, cyano, ═O, nitro, CH₃C(O)— and OHCH₂C(O)—.

As generally defined above, R_(x) is ═O or OR_(d), where R_(d) is H orC(O)R_(e), where R_(e) is optionally substituted C₁-C₂₂ alkyl oroptionally substituted C₂-C₂₂ alkenyl (including for example optionallysubstituted C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄,C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, or C₂₂ alkyl or C₂, C₃, C₄, C₅, C₆,C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁,or C₂₂ alkenyl), with the proviso that when R_(x) is OH, it is in thebeta (up) configuration. In certain embodiments, R_(x) is ═O. In certainembodiments, R_(x) is OH in the beta (up) configuration. In certainembodiments, R_(x) is OR_(d), R_(d) is C(O)R_(e), and R_(e) isoptionally substituted C₁-C₂₂ alkyl or optionally substituted C₂-C₂₂alkenyl, e.g., C(O)CH₃, and in such instances, the group Rx is providedin either the alpha or beta configuration (with the beta configurationbeing preferred). In certain embodiments, wherein R_(x) is OR_(d), andR_(d) is H, then R_(x) is OH in the beta (up) configuration.

As generally defined above, R₂ is ═O, H, or OR_(a), where R_(a) isselected from H, optionally substituted C₁-C₄ alkyl, or optionallysubstituted aryl, with the proviso that when R₂ is ═O, R₈ is notpresent. In certain embodiments, R₂ is ═O and R₈ is not present. Incertain embodiments, R₂ is H. In certain embodiments, R₂ is OR_(a). Incertain embodiments, R₂ is OR_(a) and R_(a) is optionally substitutedC₁, C₂, C₃ or C₄ alkyl (e.g., methyl, ethyl), optionally substitutedbenzyl, or C₁, C₂, C₃ or C₄ alkyl substituted with O-aryl, such asO-benzyl. In certain embodiments, R₂ is OR_(a) and R_(a) is optionallysubstituted aryl. In certain embodiments, R₂ is OR_(a) and R_(a) is H.

As generally defined above, R₄ is H or unsubstituted C₁-C₄ alkyl. Incertain embodiments, R₄ is H. In certain embodiments, R₄ isunsubstituted C₁, C₂, C₃ or C₄ alkyl (e.g., methyl, ethyl, n-propyl,isopropyl, or n-butyl).

As generally defined above, R₅ is substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl. Incertain embodiments, R₅ is substituted C₁-C₄ alkyl, and in particular isalkoxy-substituted C₁-C₄ alkyl. In other particular embodiments, R₅ issubstituted methyl, and more particularly is alkoxy-substituted methyl(or even more particularly is —CH₂—OR_(b), where R_(b) is C₁-C₄ alkyl,or even still more particularly is —CH₂—OCH₃). In other embodiments, R₅is optionally substituted C₂-C₄ alkenyl. In other embodiments, R₅ isoptionally substituted C₂-C₄ alkynyl.

As generally defined above, R₆ is H, optionally substituted C₁-C₄ alkyl,or optionally substituted C₁-C₄ alkoxy. In certain embodiments, R₆ is H.In certain embodiments, R₆ is optionally substituted C₁, C₂, C₃, or C₄alkyl (e.g., methyl). In certain embodiments, R₆ is optionallysubstituted C₁, C₂, C₃ or C₄ alkoxy (e.g., methoxy, ethoxy, n-propyloxy,isopropyloxy, or n-butoxy). In certain embodiments, when R₆ is anon-hydrogen group, R₆ is in the alpha (down) position. In certainpreferred embodiments, however, when R₆ is a non-hydrogen group, R₆ isin the beta (up) position.

As generally defined above, R₇ is H, optionally substituted C₁-C₄alkoxy, or an optionally substituted morpholinyl ring. In certainembodiments, R₇ is H. In certain embodiments, R₇ is optionallysubstituted C₁, C₂, C₃ or C₄ alkoxy (e.g., methoxy, ethoxy, n-propyloxy,isopropyloxy, or n-butoxy). In certain embodiments, R₇ is an optionallysubstituted morpholinyl ring. In certain embodiments, when R₇ is anon-hydrogen group, R₇ is in the alpha (down) position. In certainpreferred embodiments, however, when R₇ is a non-hydrogen group, R₇ isin the beta (up) position.

As generally defined above, R₈, when present, is H or optionallysubstituted C₁-C₄ alkyl. In certain embodiments, R₈ is H. In certainembodiments, R₈ is C₁, C₂, C₃ or C₄ optionally substituted alkyl (e.g.,methyl). In certain embodiments, when R₈ is optionally substituted C₁-C₄alkyl, R₈ is in the alpha (down) position. In certain embodiments whenR₈ is optionally substituted C₁-C₄ alkyl, R₈ is in the beta (up)position.

In certain embodiments, R₂ and R₈ are both H. In certain embodiments, R₂is OR_(a) and R₈ is H.

As generally defined above, - - - denotes an optional, additional C—Cbond, resulting in either a C═C bond between C₄-C₅ or C₅-C₆, with theproviso that when present, the C₅—H substituent is not present. Incertain embodiments, the additional C—C bond is absent, and the hydrogenat C₅ is in the alpha or beta position. In certain embodiments, theadditional C—C bond is absent, and the hydrogen at C₅ is in the alpha(down) position. In certain embodiments, the additional C—C bond isabsent, and the hydrogen at C₅ is in the beta (up) position. In certainembodiments, - - - denotes an additional C—C bond, resulting in a C═Cbond between C₄-C₅. In certain embodiments, - - - denotes an additionalC—C bond, resulting in a C═C bond between C₅-C₆.

As generally defined above, - - - denotes an optional, additional C—Cbond, resulting in a C═C bond, between C₁₆-C₁₇, with the proviso thatwhen present, the R₁ is other than ═O. In certain embodiments, theadditional C—C bond is absent (i.e., there is not C═C bond), andtherefore R₁ may be in the alpha or beta position. In certainembodiments, the additional C—C bond is absent, and the R₁ is in thealpha (down) position. In certain embodiments, the additional C—C bondis absent, and the R₁ is in the beta (up) position.

In certain embodiments, prodrugs of the present disclosure may beselected from among those encompassed by the structure of Formula (II),wherein R₂ is ═O. In certain embodiments, R₂ is H and R₈ is H, e.g., C₁₁thus having two hydrogen atoms bound thereto as substituents. In certainembodiments, R₂ may be OR_(a), wherein R_(a) is methyl, optionallysubstituted benzyl, or C₁-C₄ alkyl substituted with O-aryl, such asO-benzyl. In certain embodiments, R_(x) is ═O. In certain embodiments,R_(x) is β-hydroxy. In certain embodiments, R_(x) is OR_(d), where R_(d)is H or C(O)R_(e), where R_(e) is optionally substituted C₁-C₄ alkyl(e.g., methyl). In certain embodiments, each of R₄ and R₆ areindependently selected from H and methyl. In certain embodiments, R₆ isoptionally substituted alkyl, e.g., methyl, optionally in thealpha-configuration when the carbon-carbon double bond between C₅-C₆ isabsent. In certain embodiments, R₆ is optionally substituted alkyl,e.g., methyl, optionally in the beta-configuration when thecarbon-carbon double bond between C₅-C₆ is absent. In certainembodiments, R₇ is selected from H, methoxy, ethoxy, and an optionallysubstituted morpholinyl ring. In certain embodiments, R₇ is anon-hydrogen group, R₇ is in the β-position. In certain embodiments, acarbon-carbon double bond (or unsaturated bond) may be present betweenthe C₄-C₅, or C₅-C₆, carbon atoms. In certain embodiments, R₈, whenpresent, is selected from H or optionally substituted C₁-C₄ alkyl,preferably methyl and more preferably alpha-methyl.

In certain embodiments, R_(x) is OH and in the beta position. In certainembodiments, a carbon-carbon double bond is present between the C₄-C₅carbon atoms. In certain embodiments, a carbon-carbon double bond ispresent between the C₅-C₆ carbon atoms. In certain embodiments, R₂ is═O. In certain embodiments, R₂ is methoxy. In certain embodiments, R₇ isH. In certain embodiments, R₇ is β-methoxy. In certain embodiments, R₇is β-ethoxy.

In certain embodiments, wherein R₄ is methyl, R₅ is substituted methylin the beta position, and R₆ is H, provided is a compound of Formula(II-a):

or a pharmaceutically acceptable salt thereof, wherein R₁, - - - ,R_(x), R₂, R₇ (preferably in the beta configuration) and R₈ (preferablyin the beta configuration) are as defined herein, and further whereinR_(b) is optionally substituted C₁-C₄ alkyl. In certain embodiments,R_(x) is ═O. In certain embodiments, R_(x) is OH in the beta (up)configuration. In certain embodiments, each instance of - - - betweenC₅-C₆ and C₆-C₇ is absent and C₅—H is in the alpha position. In certainembodiments, each instance of - - - between C₅-C₆ and C₆-C₇ is absentand C₅—H is in the beta position. In certain embodiments, - - -represents an additional C—C bond, resulting in either a C═C bondbetween C₄-C₅ or C₅-C₆. In certain embodiments, each instance of - - -between C₁₆-C₁₇ is absent and R₁ is in the beta position. In certainembodiments, - - - represents an additional C—C bond, resulting in a C═Cbetween C₁₆-C₁₇.

In certain embodiments of Formula (II), wherein R₂ is ═O and R₈ isabsent, provided is a compound of Formula (II-b):

or a pharmaceutically acceptable salt thereof, wherein R₁, - - - ,R_(x), and R₇ (preferably in the beta configuration) are as definedherein, and further wherein R_(b) is optionally substituted C₁-C₄ alkyl.In certain embodiments, R_(x) is ═O. In certain embodiments, R_(x) is OHin the beta (up) configuration. In certain embodiments, each instanceof - - - between C₅-C₆ and C₆-C₇ is absent and C₅—H is in the alphaposition. In certain embodiments, each instance of - - - between C₅-C₆and C₆-C₇ is absent and C₅—H is in the beta position. In certainembodiments, - - - represents an additional C—C bond, resulting ineither a C═C bond between C₄-C₅ or C₅-C₆. In certain embodiments, eachinstance of - - - between C₁₆-C₁₇ is absent and R₁ is in the betaposition. In certain embodiments, - - - represents an additional C—Cbond, resulting in a C═C between C₁₆-C₁₇.

In certain embodiments of Formula (II), wherein R₂ is H and R₈ is H,provided is a compound of Formula (II-c):

or a pharmaceutically acceptable salt thereof, wherein R₁, - - - ,R_(x), and R₇ (preferably in the beta configuration) are as definedherein, and further wherein R_(b) is optionally substituted C₁-C₄ alkyl.In certain embodiments, R_(x) is ═O. In certain embodiments, R_(x) is OHin the beta (up) configuration. In certain embodiments, each instanceof - - - between C₅-C₆ and C₆-C₇ is absent and C₅—H is in the alphaposition. In certain embodiments, each instance of - - - between C₅-C₆and C₆-C₇ is absent and C₅—H is in the beta position. In certainembodiments, - - - represents an additional C—C bond, resulting ineither a C═C bond between C₄-C₅ or C₅-C₆. In certain embodiments, eachinstance of - - - between C₁₆-C₁₇ is absent and R₁ is in the betaposition. In certain embodiments, - - - represents an additional C—Cbond, resulting in a C═C between C₁₆-C₁₇.

In certain embodiments of Formula (II), wherein R₂ is OR_(a) and R₈ isH, provided is a compound of Formula (II-d):

or a pharmaceutically acceptable salt thereof, wherein R₁, - - - , R₃,R₇ (preferably in the beta configuration), and R_(a) are as definedherein, and further wherein R_(b) is optionally substituted C₁-C₄ alkyl.In certain embodiments, each instance of - - - is absent C₅—H is in thealpha position. In certain embodiments, each instance of - - - is absentC₅—H is in the beta position. In certain embodiments, - - - representsan additional C—C bond, resulting in either a C═C bond between C₄-C₅ orC₅-C₆. In certain embodiments, each instance of - - - between C₁₆-C₁₇ isabsent and R₁ is in the beta position. In certain embodiments, - - -represents an additional C—C bond, resulting in a C═C between C₁₆-C₁₇.

In certain embodiments of Formula (II), wherein R₇ is H, provided is acompound of Formula (II-e):

or a pharmaceutically acceptable salt thereof, wherein R₁, - - - ,R_(x), R₂ and R₈ (preferably in the beta configuration) are as definedherein, and further wherein R_(b) is optionally substituted C₁-C₄ alkyl.In certain embodiments, R_(x) is ═O. In certain embodiments, R_(x) is OHin the beta (up) configuration. In certain embodiments, each instanceof - - - is absent C₅—H is in the alpha position. In certainembodiments, each instance of - - - is absent C₅—H is in the betaposition. In certain embodiments, - - - represents an additional C—Cbond, resulting in either a C═C bond between C₄-C₅ or C₅-C₆. In certainembodiments, each instance of - - - between C₁₆-C₁₇ is absent and R₁ isin the beta position. In certain embodiments, - - - represents anadditional C—C bond, resulting in a C═C between C₁₆-C₁₇.

In certain embodiments of Formula (II), wherein each instance of - - -is absent C₅—H is in the alpha position, provided is a compound ofFormula (II-f):

or a pharmaceutically acceptable salt thereof, wherein R₁, R_(x), R₂, R₇(preferably in the beta configuration) and R₈ (preferably in the betaconfiguration) are as defined herein, and further wherein R_(b) isoptionally substituted C₁-C₄ alkyl. In certain embodiments, R_(x) is ═O.In certain embodiments, R_(x) is OH in the beta (up) configuration. Incertain embodiments, each instance of - - - between C₁₆-C₁₇ is absentand R₁ is in the beta position. In certain embodiments, - - - representsan additional C—C bond, resulting in a C═C between C₁₆-C₁₇.

In certain embodiments of Formula (II), wherein R₇ is H, provided is acompound of Formula (II-g):

or a pharmaceutically acceptable salt thereof, wherein R₁, R_(x), R₂ andR₈ (preferably in the beta configuration) are as defined herein, andfurther wherein R_(b) is optionally substituted C₁-C₄ alkyl. In certainembodiments, R_(x) is ═O. In certain embodiments, R_(x) is OH in thebeta (up) configuration. In certain embodiments, each instance of - - -between C₁₆-C₁₇ is absent and R₁ is in the beta position. In certainembodiments, - - - represents an additional C—C bond, resulting in a C═Cbetween C₁₆-C₁₇.

In certain embodiments of Formula (II), wherein R₂ is ═O, provided is acompound of Formula (II-h):

or a pharmaceutically acceptable salt thereof, wherein R₁, R_(x) and R₇(preferably in the beta configuration) are as defined herein, andfurther wherein R_(b) is optionally substituted C₁-C₄ alkyl. In certainembodiments, R_(x) is ═O. In certain embodiments, R_(x) is OH in thebeta (up) configuration. In certain embodiments, each instance of - - -between C₁₆-C₁₇ is absent and R₁ is in the beta position. In certainembodiments, - - - represents an additional C—C bond, resulting in a C═Cbetween C₁₆-C₁₇.

In certain embodiments of Formula (II), wherein R₂ is OR_(a), providedis a compound of Formula (II-i):

or a pharmaceutically acceptable salt thereof, wherein R₁, R_(x), R_(a),and R₇ (preferably in the beta configuration) are as defined herein, andfurther wherein R_(b) is optionally substituted C₁-C₄ alkyl. In certainembodiments, R_(x) is ═O. In certain embodiments, R_(x) is OH in thebeta (up) configuration. In certain embodiments, each instance of - - -between C₁₆-C₁₇ is absent and R₁ is in the beta position. In certainembodiments, - - - represents an additional C—C bond, resulting in a C═Cbetween C₁₆-C₁₇.

In certain embodiments of Formula (II), wherein - - - represents anadditional C—C bond, resulting in a C═C bond between C₄-C₅ provided is acompound of Formula (II-j):

or a pharmaceutically acceptable salt thereof, wherein R₁, R_(x), R₂, R₇(preferably in the beta configuration) and R₈ (preferably in the betaconfiguration) are as defined herein, and further wherein R_(b) isoptionally substituted C₁-C₄ alkyl. In certain embodiments, R_(x) is ═O.In certain embodiments, R_(x) is OH in the beta (up) configuration. Incertain embodiments, each instance of - - - between C₁₆-C₁₇ is absentand R₁ is in the beta position. In certain embodiments, - - - representsan additional C—C bond, resulting in a C═C between C₁₆-C₁₇.

In certain embodiments of Formula (II), wherein - - - represents anadditional C—C bond, resulting in a C═C bond between C₅-C₆ provided is acompound of Formula (II-k):

or a pharmaceutically acceptable salt thereof, wherein R₁, R_(x), R₂, R₇(preferably in the beta configuration) and R₈ (preferably in the betaconfiguration) are as defined herein, and further wherein R_(b) isoptionally substituted C₁-C₄ alkyl. In certain embodiments, R_(x) is ═O.In certain embodiments, R_(x) is OH in the beta (up) configuration. Incertain embodiments, each instance of - - - between C₁₆-C₁₇ is absentand R₁ is in the beta position. In certain embodiments, - - - representsan additional C—C bond, resulting in a C═C between C₁₆-C₁₇.

It is to be noted that, in one or more of the preferred embodimentsdetailed above, R₁ may, in particular, be selected from methoxy (or moregenerally lower alkoxy, e.g., —O—(C₁-C₄)), or alternatively selectedfrom CH₃C(O)— or HOCH₂C(O)— (or more generally substituted orunsubstituted lower alkyl-carbonyl, e.g., (C₁-C₄)C(O)—, wherein one ormore of the carbon atoms is optionally substituted, such as for exampleby a hydroxyl group). Alternatively, R₁ may be selected from nitro orcyano, with an optional C═C being present between C₁₆-C₁₇. In yetanother alternative embodiment, C₁₇ may be a carbonyl carbon (i.e., R₁is ═O), or it may be part of an oxirane ring fused with the D-ring(i.e., R₁ being a spirooxirane substituent, wherein C₁₇ is the carbonatom common to both rings).

Exemplary compounds of Formula (II) include, but are not limited to:

and pharmaceutically acceptable salts thereof, wherein in one preferredembodiment R_(b) is CH₃.

In this regard it is to be noted that the structures provided above areof various exemplary embodiments. As such, they should not be viewed ina limiting sense.

3. Methods of Preparation and Pharmaceutical Compositions

It is to be noted that the compounds or steroids of the presentdisclosure, or the prodrugs thereof, may in various embodiments beprepared or used in accordance with means generally known in the art.For example, in certain embodiments, the steroids or prodrugs of thepresent disclosure may be prepared or used in a pharmaceuticallyacceptable salt form, for example, where R₇ is an optionally substitutedmorpholinyl ring. Suitable salt forms include, for example, citrate orchloride salt forms.

In various embodiments of the present disclosure, a pharmaceuticalcomposition is disclosed that may comprise a steroid, a prodrug, or acombination of two or more thereof in accordance with the formulas ofthe present disclosure. The compounds or steroids of the presentdisclosure (or the prodrugs thereof), as well as the various salt formsand other pharmaceutically acceptable forms, e.g., solvates and/orhydrates of compounds described herein, and pharmaceutical compositionscontaining them, may in general be prepared using methods and techniquesknown in the art, and/or as described in the Examples provided herein.

Without wishing to be bound by any particular theory, the compounds orsteroids of the present disclosure are useful for potentiating GABA atGABA_(A) receptors thereby inducing anesthesia or treating disordersrelated to GABA function (e.g., insomnia, mood disorders, convulsivedisorders, anxiety disorders, or symptoms of ethanol withdrawal) in asubject, e.g., a human subject, and are preferably administered in theform of a pharmaceutical composition comprising an effective amount of acompound of the instant disclosure and optionally a pharmaceutically orpharmacologically acceptable carrier.

In one aspect, provided is a method of inducing anesthesia in a subjectin need thereof, the method comprising administering to the subject atherapeutically effective amount of one or more of the above-notedsteroids, or prodrugs, or pharmaceutically acceptable salts thereof, ora pharmaceutical composition thereof.

In another aspect, provided is a method of treating disorders related toGABA function in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of oneor more of the above-noted steroids, or prodrugs, or pharmaceuticallyacceptable salts thereof, or a pharmaceutical composition thereof. Incertain embodiments, the disorder is selected from the group consistingof insomnia, mood disorders, convulsive disorders, anxiety, or symptomsof ethanol withdrawal.

In one embodiment of the present disclosure, a therapeutically effectiveamount of compound is from about 5 mg/kg to about 20 mg/kg, about 5mg/kg to about 18 mg/kg, about 5 mg/kg to about 16 mg/kg, about 5 mg/kgto about 14 mg/kg, about 5 mg/kg to about 12 mg/kg, about 5 mg/kg toabout 10 mg/kg, about 6 mg/kg to about 10 mg/kg, about 6 mg/kg to about9 mg/kg, about 7 mg/kg to about 9 mg/kg, or about 8 mg/kg to about 16mg/kg. In certain embodiments, a therapeutically effective amount of thecompound is about 8 mg/kg. It will be appreciated that dose ranges asdescribed herein provide guidance for the administration of providedpharmaceutical compositions to an adult. The amount to be administeredto, for example, a child or an adolescent can be determined by a medicalpractitioner or person skilled in the art and can be lower or the sameas that administered to an adult.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, identity of the particularcompound(s), mode of administration, and the like. The desired dosagecan be delivered three times a day, two times a day, once a day, everyother day, every third day, every week, every two weeks, every threeweeks, or every four weeks. In certain embodiments, the desired dosagecan be delivered using multiple administrations (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or more administrations).

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionaltherapeutically active agents. The compounds or compositions can beadministered in combination with additional therapeutically activeagents that improve their bioavailability, reduce and/or modify theirmetabolism, inhibit their excretion, and/or modify their distributionwithin the body.

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional therapeutically activeagents. In general, each agent will be administered at a dose and/or ona time schedule determined for that agent. It will further beappreciated that the additional therapeutically active agent utilized inthis combination can be administered together in a single composition oradministered separately in different compositions. The particularcombination to employ in a regimen will take into account compatibilityof the inventive compound with the additional therapeutically activeagent and/or the desired therapeutic effect to be achieved. In general,it is expected that additional therapeutically active agents utilized incombination be utilized at levels that do not exceed the levels at whichthey are utilized individually. In some embodiments, the levels utilizedin combination will be lower than those utilized individually. Exemplarytherapeutically active agents include small organic molecules such asdrug compounds (e.g., compounds approved by the US Food and DrugAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins and cells.

The pharmaceutical composition may also be in combination with at leastone pharmacologically acceptable carrier. The carrier, also known in theart as an excipient, vehicle, auxiliary, adjuvant, or diluent, is anysubstance that is pharmaceutically inert, confers a suitable consistencyor form to the composition, and does not diminish the therapeuticefficacy of the compounds. The carrier is “pharmaceutically orpharmacologically acceptable” if it does not produce an adverse,allergic, or other untoward reaction when administered to a mammal orhuman, as appropriate.

The pharmaceutical compositions containing the compounds or steroids ofthe present disclosure may be formulated in any conventional manner.Proper formulation is dependent upon the route of administration chosen.The compositions of the disclosure can be formulated for any route ofadministration, so long as the target tissue is available via thatroute. Suitable routes of administration include, but are not limitedto, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous,rectal, subcutaneous, intramuscular, intraorbital, intracapsular,intraspinal, intraperitoneal, or intrasternal), topical (nasal,transdermal, intraocular), intravesical, intrathecal, enteral,pulmonary, intralymphatic, intracavital, vaginal, transurethral,intradermal, aural, intramammary, buccal, orthotopic, intratracheal,intralesional, percutaneous, endoscopical, transmucosal, sublingual, andintestinal administration. In certain embodiments, the route ofadministration is oral. In certain embodiments, the route ofadministration is parenteral. In certain embodiments, the route ofadministration is intravenous.

Pharmaceutically acceptable carriers for use in the compositions of thepresent disclosure are well known to those of ordinary skill in the artand are selected based upon a number of factors, including for example:the particular compound used, and its concentration, stability andintended bioavailability; the disease, disorder or condition beingtreated with the composition; the subject, its age, size and generalcondition; and/or the route of administration. Suitable carriers may bereadily determined by one of ordinary skill in the art. (See, forexample, J. G. Nairn, in: Remington's Pharmaceutical Science (A.Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp. 1492-1517.)

The compositions may be formulated as tablets, dispersible powders,pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions,suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, orany other dosage form that can be administered orally. Techniques andcompositions for making oral dosage forms useful in the presentdisclosure are described in the following exemplary references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and,Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

The compositions of the present disclosure designed for oraladministration comprise an effective amount of a compound of thedisclosure in a pharmaceutically acceptable carrier. Suitable carriersfor solid dosage forms include sugars, starches, and other conventionalsubstances including lactose, talc, sucrose, gelatin,carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate,calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, cornstarch, potato starch, sodium saccharin, magnesium carbonate,tragacanth, microcrystalline cellulose, colloidal silicon dioxide,croscarmellose sodium, talc, magnesium stearate, and stearic acid.Further, such solid dosage forms may be uncoated or may be coated byknown techniques (e.g., to delay disintegration and absorption).

The compounds, steroids, and prodrugs of the present disclosure may alsobe formulated for parenteral administration (e.g., formulated forinjection via intravenous, intraarterial, subcutaneous, rectal,subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal routes). The compositions of thepresent disclosure for parenteral administration comprise an effectiveamount of the compound in a pharmaceutically acceptable carrier. Dosageforms suitable for parenteral administration include solutions,suspensions, dispersions, emulsions or any other dosage form that can beadministered parenterally. Techniques and compositions for makingparenteral dosage forms are known in the art. Typically formulations forparenteral administration are sterile or are sterilized beforeadministration.

Suitable carriers used in formulating liquid dosage forms for oral orparenteral administration include nonaqueous,pharmaceutically-acceptable polar solvents such as oils, alcohols,amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, aswell as water, saline solutions, dextrose solutions (e.g., DW5),electrolyte solutions, or any other aqueous, pharmaceutically acceptableliquid.

Suitable nonaqueous, pharmaceutically-acceptable polar solvents include,but are not limited to, alcohols (e.g., α-glycerol formal, β-glycerolformal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol,t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin(glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, laurylalcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fattyalcohols such as polyalkylene glycols (e.g., polypropylene glycol,polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g.,dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide,N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide, 2-pyrrolidinone,1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g.,1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esters such asmonoacetin, diacetin, and triacetin, aliphatic or aromatic esters suchas ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzylacetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di,or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate,ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters ofsorbitan, fatty acid derived PEG esters, glyceryl monostearate,glyceride esters such as mono, di, or tri-glycerides, fatty acid esterssuch as isopropyl myristrate, fatty acid derived PEG esters such asPEG-hydroxyoleate and PEG-hydroxystearate, N-methyl pyrrolidinone,pluronic 60, polyoxyethylene sorbitol oleic polyesters such aspoly(ethoxylated)₃₀₋₆₀ sorbitol poly(oleate)₂₋₄, poly(oxyethylene)₁₅₋₂₀monooleate, poly(oxyethylene)₁₅₋₂₀ mono 12-hydroxystearate, andpoly(oxyethylene)₁₅₋₂₀ mono-ricinoleate, polyoxyethylene sorbitan esters(such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitanmonopalmitate, polyoxyethylene-sorbitan monolaurate,polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80from ICI Americas, Wilmington, Del.), polyvinylpyrrolidone, alkyleneoxymodified fatty acid esters (such as polyoxyl 40 hydrogenated castor oil,cyclodextrins or modified cyclodextrins (e.g.,beta-hydroxypropyl-cyclodextrin)), saccharide fatty acid esters (i.e.,the condensation product of a monosaccharide (e.g., pentoses, such asribose, ribulose, arabinose, xylose, lyxose and xylulose, hexoses suchas glucose, fructose, galactose, mannose and sorbose, trioses, tetroses,heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactoseand trehalose) or oligosaccharide or mixture thereof with a C₄-C₂₂ fattyacid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid and stearic acid, andunsaturated fatty acids such as palmitoleic acid, oleic acid, elaidicacid, erucic acid and linoleic acid)), or steroidal esters); alkyl,aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether,tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethylether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycolether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethylketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatichydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane,dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane,sulfolane, tetramethylenesulfone, tetramethylenesulfoxide, toluene,dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral,vegetable, animal, essential or synthetic origin (e.g., mineral oilssuch as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons,mixed aliphatic and aromatic based hydrocarbons, and refined paraffinoil, vegetable oils such as linseed, tung, safflower, soybean, castor,cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ,sesame, persic and peanut oil and glycerides such as mono-, di- ortriglycerides, animal oils such as fish, marine, sperm, cod-liver,haliver, squalene, squalane, and shark liver oil, oleic oils, andpolyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbonatoms and optionally more than one halogen substituent; methylenechloride; monoethanolamine; petroleum benzine; trolamine; omega-3polyunsaturated fatty acids (e.g., alpha-linolenic acid,eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid);polyglycol ester of 12-hydroxystearic acid and polyethylene glycol(Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethyleneglycerol; sodium laurate; sodium oleate; or sorbitan monooleate.

Other pharmaceutically acceptable solvents for use in the disclosure arewell known to those of ordinary skill in the art, and are identified inThe Handbook of Pharmaceutical Excipients, (American PharmaceuticalAssociation, Washington, D.C., and The Pharmaceutical Society of GreatBritain, London, England, 1968), Modern Pharmaceutics, (G. Banker etal., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y., 1995), ThePharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw HillPublishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.,)(Marcel Dekker, Inc., New York, N.Y., 1980), Remington's PharmaceuticalSciences (A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, Pa.,1995), The United States Pharmacopeia 24, The National Formulary 19,(National Publishing, Philadelphia, Pa., 2000), A. J. Spiegel et al.,and Use of Nonaqueous Solvents in Parenteral Products, J. of Pharm.Sciences, Vol. 52, No. 10, pp. 917-927 (1963).

Preferred solvents include cyclodextrins or modified cyclodextrins(e.g., beta-hydroxypropyl-cyclodextrin) as well as oils rich intriglycerides, for example, safflower oil, soybean oil or mixturesthereof, and alkyleneoxy modified fatty acid esters such as polyoxyl 40hydrogenated castor oil. Commercially available triglycerides includeIntralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm,Sweden), Nutralipid® emulsion (McGaw, Irvine, Calif.), Liposyn® II 20%emulsion (a 20% fat emulsion solution containing 100 mg safflower oil,100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), Liposyn® III 2% emulsion(a 2% fat emulsion solution containing 100 mg safflower oil, 100 mgsoybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), natural or syntheticglycerol derivatives containing the docosahexaenoyl group at levelsbetween 25% and 100% by weight based on the total fatty acid content(Dhasco® (from Martek Biosciences Corp., Columbia, Md.), DHA Maguro®(from Daito Enterprises, Los Angeles, Calif.), Soyacal®, andTravemulsion®.

Additional minor components can be included in the compositions of thedisclosure for a variety of purposes well known in the pharmaceuticalindustry. These components will for the most part impart propertieswhich enhance retention of the compound at the site of administration,protect the stability of the composition, control the pH, facilitateprocessing of the compound into pharmaceutical formulations, and thelike. Preferably, each of these components is individually present inless than about 15 wt % of the total composition, more preferably lessthan about 5 wt %, and most preferably less than about 0.5 wt % of thetotal composition. Some components, such as fillers or diluents, canconstitute up to 90 wt % of the total composition, as is well known inthe formulation art. Such additives include cryoprotective agents forpreventing reprecipitation, surface active, wetting or emulsifyingagents (e.g., lecithin, polysorbate-80, Tween® 80, Pluronic 60,polyoxyethylene stearate), preservatives (e.g.,ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol,phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben),agents for adjusting pH or buffering agents (e.g., acids, bases, sodiumacetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g.,glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetylalcohol, stearyl alcohol, guar gum, methyl cellulose,hydroxypropylcellulose, tristearin, cetyl wax esters, polyethyleneglycol), colorants, dyes, flow aids, non-volatile silicones (e.g.,cyclomethicone), clays (e.g., bentonites), adhesives, bulking agents,flavorings, sweeteners, adsorbents, fillers (e.g., sugars such aslactose, sucrose, mannitol, or sorbitol, cellulose, or calciumphosphate), diluents (e.g., water, saline, electrolyte solutions),binders (e.g., starches such as maize starch, wheat starch, rice starch,or potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropyl methylcellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents(e.g., starches such as maize starch, wheat starch, rice starch, potatostarch, or carboxymethyl starch, cross-linked polyvinyl pyrrolidone,agar, alginic acid or a salt thereof such as sodium alginate,croscarmellose sodium or crospovidone), lubricants (e.g., silica, talc,stearic acid or salts thereof such as magnesium stearate, orpolyethylene glycol), coating agents (e.g., concentrated sugar solutionsincluding gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, or titanium dioxide), and antioxidants (e.g.,sodium metabisulfite, sodium bisulfate, sodium sulfite, dextrose,phenols, and thiophenols).

Dosage from administration by these routes may be continuous orintermittent, depending, for example, upon the patient's physiologicalcondition, whether the purpose of the administration is therapeutic orprophylactic, and other factors known to and assessable by a skilledpractitioner.

Those with ordinary skill in administering anesthetics can readilydetermine dosage and regimens for the administration of thepharmaceutical compositions of the disclosure or titrating to aneffective dosage for use in treating insomnia, mood disorders,convulsive disorders, anxiety or symptoms of ethanol withdrawal. It isunderstood that the dosage of the compounds will be dependent upon theage, sex, health, and weight of the recipient, kind of concurrenttreatment, if any, frequency of treatment, and the nature of the effectdesired. For any mode of administration, the actual amount of compounddelivered, as well as the dosing schedule necessary to achieve theadvantageous effects described herein, will also depend, in part, onsuch factors as the bioavailability of the compound, the disorder beingtreated, the desired therapeutic dose, and other factors that will beapparent to those of skill in the art. The dose administered to ananimal, particularly a human, in the context of the present disclosureshould be sufficient to affect the desired therapeutic response in theanimal over a reasonable period of time. Preferably, an effective amountof the compound, whether administered orally or by another route, is anyamount that would result in a desired therapeutic response whenadministered by that route. The dosage may vary depending on the dosingschedule, which can be adjusted as necessary to achieve the desiredtherapeutic effect. The most preferred dosage will be tailored to theindividual subject, as is understood and determinable by one of ordinaryskill in the art without undue experimentation.

In one embodiment, solutions for oral administration are prepared bydissolving the compound in any pharmaceutically acceptable solventcapable of dissolving a compound (e.g., ethanol or methylene chloride)to form a solution. An appropriate volume of a carrier which is asolution, such as beta-hydroxypropyl-cyclodextrin, is added to thesolution while stirring to form a pharmaceutically acceptable solutionfor oral administration to a patient. If desired, such solutions can beformulated to contain a minimal amount of, or to be free of, ethanol,which is known in the art to cause adverse physiological effects whenadministered at certain concentrations in oral formulations.

In another embodiment, powders or tablets for oral administration areprepared by dissolving a compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. The solvent can optionally be capable ofevaporating when the solution is dried under vacuum. An additionalcarrier can be added to the solution prior to drying, such asbeta-hydroxypropyl-cyclodextrin. The resulting solution is dried undervacuum to form a glass. The glass is then mixed with a binder to form apowder. The powder can be mixed with fillers or other conventionaltabletting agents and processed to form a tablet for oral administrationto a patient. The powder can also be added to any liquid carrier asdescribed above to form a solution, emulsion, suspension or the like fororal administration.

Emulsions for parenteral administration can be prepared by dissolving acompound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is an emulsion, suchas Liposyn® II or Liposyn® III emulsions, is added to the solution whilestirring to form a pharmaceutically acceptable emulsion for parenteraladministration to a patient.

Solutions for parenteral administration can be prepared by dissolving acompound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is a solution, suchas beta-hydroxypropyl-cyclodextrin, is added to the solution whilestirring to form a pharmaceutically acceptable solution for parenteraladministration to a patient.

If desired, the emulsions or solutions described above for oral orparenteral administration can be packaged in IV bags, vials or otherconventional containers in concentrated form and diluted with anypharmaceutically acceptable liquid, such as saline, to form anacceptable concentration prior to use as is known in the art.

Still further encompassed by the invention are kits (e.g.,pharmaceutical packs). The kits provided may comprise a compound asdescribed herein and a container (e.g., a vial, ampule, bottle, syringe,and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical carrier for dilution or suspensionof the pharmaceutical composition or compound. In some embodiments, thepharmaceutical composition or compound provided in the container and thesecond container are combined to form one unit dosage form.

Optionally, instructions for use are additionally provided in such kitsof the invention. Such instructions may provide, generally, for example,instructions for dosage and administration. In other embodiments,instructions may further provide additional detail relating tospecialized instructions for particular containers and/or systems foradministration. Still further, instructions may provide specializedinstructions for use in conjunction and/or in combination with anadditional therapeutic agent.

4. Definitions

The term “steroid” as used herein describes an organic compoundcontaining in its chemical nucleus the cyclopenta[a]phenanthrene ringsystem.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

The term “prodrug” as used herein describes a pharmacological substancethat is administered in a less active or inactive form. Afteradministration, a prodrug is metabolized in vivo e.g., via hydrolysis,oxidation, or reaction under biological conditions (in vitro or invivo), to provide an active metabolite. See, e.g., Wu, Pharmaceuticals(2009) 2:77-81. In certain embodiments, a prodrug has improved physicaland/or delivery properties over the parent compound. Prodrugs aretypically designed to enhance pharmaceutically and/orpharmacokinetically based properties associated with the parentcompound. The advantage of a prodrug can lie in its physical properties,such as enhanced water solubility for parenteral administration atphysiological pH compared to the parent compound, or it enhancesabsorption from the digestive tract or the skin, or it may enhance drugstability for long-term storage.

As used herein, a “subject” to which administration is contemplatedincludes, but is not limited to, mammals, e.g., humans (i.e., a male orfemale of any age group, e.g., a pediatric subject (e.g., child,adolescent) or adult subject (e.g., young adult, middle-aged adult orsenior adult)), other primates (e.g., cynomolgus monkeys, rhesusmonkeys) and commercially relevant mammals such as cattle, pigs, horses,sheep, goats, cats, and/or dogs. In any aspect and/or embodiment of theinvention, the subject is a human.

As used herein, a “therapeutically effective amount”, “an amountsufficient” or “sufficient amount” of a compound means the level, amountor concentration of the compound required for a desired biologicalresponse, e.g., analgesia.

The term “saturated” as used herein describes the state in which allavailable valence bonds of an atom (especially carbon) are attached toother atoms.

The term “unsaturated” as used herein describes the state in which notall available valence bonds along the alkyl chain are satisfied; in suchcompounds the extra bonds usually form double or triple bonds (chieflywith carbon).

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₄ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₁₋₃, C₁₋₂, C₂₋₄, C₂₋₃ and C₃₋₄ alkyl, while“C₁₋₂₂ alkyl” is intended to encompass, for example, C₁, C₂, C₃, C₄,etc., as well as C₁₋₂₁, C₁₋₂₀, C₁₋₁₅, C₁₋₁₀, C₂₋₂₀, C₂₋₁₅, C₂₋₁₀, C₃₋₁₅,C₃₋₁₀, etc. alkyl.

As used herein, “alkyl” refers to a radical of a straight-chain orbranched saturated hydrocarbon group having from, in some embodiments, 1to 4 carbon atoms (“C₁₋₄ alkyl”), and in other embodiments 1 to 22carbon atoms (“C₁₋₂₂ alkyl”). In some embodiments, an alkyl group has 1to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl grouphas 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkylgroup has 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkylgroup has 2 to 4 carbon atom (“C₂₋₄ alkyl”). In yet other embodiments,an alkyl group has 1 to 21 carbon atoms (“C₁₋₂₁ alkyl”), 1 to 20 carbonatoms (“C₁₋₂₀ alkyl”), 1 to 15 carbon atoms (“C₁₋₁₅ alkyl”), 1 to 10carbon atoms (“C₁₋₁₀ alkyl”), etc. Examples of such alkyl groups includemethyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄),tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), pentyl (C₅), and thelike.

As used herein, “alkenyl” or “alkene” refers to a radical of astraight-chain or branched hydrocarbon group having from, in someembodiments, 2 to 4 carbon atoms (“C₂₋₄ alkenyl”), and in otherembodiments 2 to 22 carbon atoms (“C₂₋₂₂ alkenyl”), and one or morecarbon-carbon double bonds. In some embodiments, an alkenyl group has 2to 3 carbon atoms (“C₂₋₃ alkenyl”). In some embodiments, an alkenylgroup has 2 carbon atoms (“C₂ alkenyl”). In yet other embodiments, analkenyl group has 2 to 21 carbon atoms (“C₂₋₂₁ alkenyl”), 2 to 20 carbonatoms (“C₂₋₂₀ alkenyl”), 2 to 15 carbon atoms (“C₂₋₁₅ alkenyl”), 2 to 10carbon atoms (“C₂₋₁₀ alkyl”), etc. The one or more carbon-carbon doublebonds can be internal (such as in 2-butenyl) or terminal (such as in1-butenyl). Examples of such alkenyl groups include ethenyl (C₂),1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄),butadienyl (C₄), 1-pentenyl (C₅), 2-pentenyl (C₅), and the like.

As used herein, “alkynyl” or “alkyne” refers to a radical of astraight-chain or branched hydrocarbon group having from 2 to 4 carbonatoms and one or more carbon-carbon triple bonds (“C₂₋₁₀ alkynyl”). Insome embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14 electrons shared in a cyclic array) having 6-14 ring carbonatoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl).

As used herein, “alkoxy” refers to an alkyl, alkenyl, or alkynyl group,as defined herein, attached to an oxygen radical.

Alkyl, alkenyl, alkynyl, and aryl groups, as defined herein, aresubstituted or unsubstituted, also referred to herein as “optionallysubstituted”. In general, the term “substituted”, whether preceded bythe term “optionally” or not, means that at least one hydrogen presenton a group (e.g., a carbon or nitrogen atom) is replaced with apermissible substituent, e.g., a substituent which upon substitutionresults in a stable compound, e.g., a compound which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that result in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary substituents include groups that contain a heteroatom (such asnitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogenatom), halogen (e.g., chlorine, bromine, fluorine, or iodine), aheterocycle, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol,ketals, acetals, esters and ethers.

EXAMPLES

The following Examples describe or illustrate various embodiments of thepresent disclosure. Other embodiments within the scope of the appendedclaims will be apparent to a skilled artisan considering thespecification or practice of the disclosure as described herein. It isintended that the specification, together with the Examples, beconsidered exemplary only, with the scope and spirit of the disclosurebeing indicated by the claims, which follow the Example.

A. Compound Chemistry

In accordance with the following methods and Examples, the followingcompounds were prepared for purposes of illustration:

In accordance with Scheme 1, the following compounds were prepared,using methods generally known in the art and as outlined below.

19-[[(1,1-Dimethyl)dimethylsilyl]oxy]-androst-4-ene-3,17-dione (1)

A mixture of the known 19-hydroxyandrostenedione (1 g, 3.31 mmol),tert-butyldimethylsilyl chloride (602 mg, 4 mmol), imidazole (315 mg,4.63 mmol), DMF (5 mL) and methylene chloride (5 mL) was stirred at roomtemperature for 15 h. Water (100 mL) was added to the reaction mixtureand extracted with methylene chloride (50 mL×3). The combined organicextracts were washed with brine, dried and concentrated to give a whitesolid. The solid was purified by flash column chromatography (silica geleluted with 10-20% EtOAc in hexanes) to give a white solid (1.3 g, 94%):mp 154-156° C.; IR 2856, 2930, 1739, 1670, 1472, 1359, 1255, 1228 cm⁻¹;¹H NMR (CDCl₃) δ 5.85 (s, 1H), 3.87 (dd, J=12.9, 10.0 Hz, 2H), 2.65-0.95(m), 0.89 (s, 3H), 0.83 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); ¹³C NMR(CDCl₃) δ 220.0, 199.6, 167.2, 126.0, 65.8, 54.0, 51.3, 47.5, 43.5,35.9, 35.6, 34.6, 33.5, 33.2, 31.7, 30.7, 25.7 (3×C), 21.6, 20.9, 18.0,13.8, −5.76, −5.83.

(5α)-19-[[(Dimethylethyl)dimethylsilyl]oxy]-androstane-3,17-dione (2)

Lithium wire in small pieces (140 mg, 20 mmol) was added to a stirredcold solution (−78° C.) of freshly condensed liquid ammonia (250 mL) andthe mixture was stirred for 15 min. Steroid 1 (1.25 g, 3 mmol) in THF(75 mL) was added to the resulting deep blue solution and stirring wascontinued at −78° C. for 2 h. Solid ammonium chloride (5 g) was addedand the ammonia was allowed to evaporate. Water (200 mL) was added andthe reaction mixture was extracted with EtOAc (100 mL×3). The combinedEtOAc extracts were washed with brine, dried and concentrated to give anoil. The oil was dissolved in stirred acetone (50 mL) and cooled in anice bath. Jones reagent was added to the stirred cold solution until anorange color persisted for 1 h. The excess Jones reagent was reduced byadding few drops of isopropyl alcohol. The acetone was removed underreduced pressure and the resulting solution was diluted with water (200mL) and extracted with EtOAc (80 mL×3). The combined EtOAc extracts weredried and removed to give a white solid which was purified bychromatography (silica gel) to yield steroid 2 (830 mg, 63%): mp130-132° C.; IR 3339, 2922, 2857, 1445, 1360 cm⁻¹; ¹H NMR (CDCl₃) δ 3.87(dd, J=21.2, 10.0 Hz, 2H), 2.60-0.70 (m), 0.87 (s, 9H), 0.07 (s, 3H),0.06 (s, 3H); ¹³C NMR (CDCl₃) δ 220.6, 211.8, 60.9, 54.3, 51.6, 47.7,46.1, 44.8, 39.4, 38.5, 35.7, 35.4, 33.9, 31.9, 30.5, 28.3, 25.7 (3×C),21.7, 18.0, 13.8, −5.7, −5.9.

(5α)-19-[[(Dimethylethyl)dimethylsilyl]oxy]-androstane-3,17-dione,3-cyclic 1,2-ethandiyl acetal (3)

A solution of steroid 2 (4.6 g, 11.0 mmol) in benzene (˜100 mL)containing ethylene glycol (5 mL) and PPTS (500 mg) was heated underreflux with Dean-Stark apparatus for 4 h. The solvent was removed underreduced pressure and the residue was purified by column chromatography(silica gel eluted with 20% EtOAc in hexanes) to give the 3,17-bisketal(3.5 g) and steroid 3 as a solidified foam (1.25 g): ¹H NMR (CDCl₃) δ3.85-3.90 (m, 4H), 3.81 (d, J=10.6 Hz, 1H), 3.65 (d, J=10.6 Hz, 1H),2.36-0.76 (m), 0.83 (s, 9H), 0.10 (d, J=3.9 Hz, 6H); ¹³C NMR (CDCl₃) δ221.2, 109.1, 64.1, 60.3, 59.9, 54.5, 51.8, 47.8, 43.6, 39.2, 38.3,35.7, 35.4, 32.0, 31.3, 30.7, 30.6, 27.8, 25.7, 21.7, 20.9, 17.0, 14.1,−5.7, −5.9; Anal. Calcd for C₂₇H₄₆O₄Si: C, 70.08; H, 10.02. Found: C,69.89; H, 10.0.

(5α)-19-Hydroxyandrostane-3,17-dione, 3-cyclic 1,2-ethandiyl acetal (4)

To a solution of steroid 3 (1.0 g, 2.4 mmol) in THF (10 mL) was addedTBAF (6.0 mmol, 1.0 M in THF, 6.0 mL) at room temperature. The reactionmixture was refluxed for 16 h and the solvent was removed under reducedpressure and the residue was purified by column chromatography (silicagel eluted with 30% EtOAc in hexanes) to give steroid 4 as an oil (638mg, 84%): IR ν_(max) 3487, 1738 cm⁻¹; ¹H NMR (CDCl₃) δ 3.90-3.85 (m,4H), 3.86 (d, J=11.4 Hz, 1H), 3.78 (d, J=11.4 Hz, 1H), 2.42-0.76 (m),0.86 (s, 3H); ¹³C NMR (CDCl₃) δ 221.4, 108.9, 64.1, 64.0, 60.0, 54.4,51.6, 47.8, 43.7, 39.2, 38.2, 35.7, 35.4, 31.9, 31.4, 30.6, 30.1, 27.7,21.9, 21.7, 13.9.

(5α,17β)-17,17-Dihydroxyandrostan-3-one, cyclic 1,2-ethandiyl acetal (5)

To a solution of steroid 4 (635 mg, 1.8 mmol) in ethanol (40 mL) wasadded sodium borohydride (152 mg, 4 mmol) at room temperature. After 3h, the mixture was quenched by aqueous NH₄Cl. The mixture was extractedwith EtOAc (50 mL×3), the organic layers were combined and dried overMgSO₄, filtered, and concentrated. The residue was purified by columnchromatography (silica gel eluted with 35% EtOAc in hexanes) to givesteroid 5 as an oil (638 mg, 100%): ¹H NMR (CDCl₃) δ 3.92-3.90 (m, 5H),3.90 (d, J=12.4 Hz, 1H), 3.61 (t, J=8.6 Hz, 1H), 2.22-0.73 (m), 0.76 (s,3H); ¹³C NMR (CDCl₃) δ 109.1, 81.8, 64.2, 64.1, 60.2, 54.4, 51.3, 43.8,43.1, 39.3, 38.3, 37.2, 36.0, 31.6, 31.3, 30.4, 30.1, 27.9, 23.4, 22.5,11.4.

(5α,17β)-17,19-Dimethoxyandrostan-3-one, cyclic 1,2-ethandiyl acetal (6)

To a solution of steroid 5 (635 mg, 1.8 mmol) in THF (30 mL) was addedsodium hydride (400 mg, 60% in mineral oil, 6.0 mmol). After addition,the mixture was refluxed for 1 h, iodomethane was added and refluxed foran additional 3 h. After cooling down to room temperature, the mixturewas quenched by water and extracted with EtOAc (100 mL×3). The organicextracts were combined and dried over with MgSO₄, filtered, andconcentrated. The residue was purified by column chromatography (silicagel eluted with 20% EtOAc in hexanes) to give steroid 6 (623 mg, 92%):mp 102-104° C.; IR ν_(max) 2922, 1448 cm⁻¹; ¹H NMR (CDCl₃) δ 3.84 (m,4H), 3.43 (d, J=9.4 Hz, 1H), 3.36 (d, J=9.4 Hz, 1H), 3.24 (s, 3H), 3.21(s, 3H), 3.12 (t, J=7.8 Hz, 1H), 2.10-0.63 (m), 0.68 (3H); ¹³C NMR(CDCl₃) δ 109.1, 90.6, 70.9, 64.0 (2×C), 58.9, 57.6, 54.2, 51.3, 43.7,42.9, 38.8, 38.3, 38.2, 35.6, 31.4, 31.3, 30.9, 28.0, 27.5, 23.2, 21.9,11.5.

(5α,17β)-17,19-Dimethoxyandrostan-3-one (7, MQ-88).

The mixture of steroid 6 (625 mg, 1.65 mmol), PTSA (100 mg), acetone (30ml) and water (3 mL) was stirred at room temperature for 16 h. Solventswere removed by reduced pressure, aqueous NaHCO₃ was added and theproduct extracted into EtOAc (100 mL×3). The organic layers werecombined, dried over with MgSO₄, filtered, and concentrated. The residuewas purified by column chromatography (silica gel eluted with 20% EtOAcin hexanes) to give steroid 7 (408 mg, 74%): mp 91-93° C.; [α]_(D)²⁰=18.4 (c=0.37, CHCl₃); ν_(max) 2922, 1714 cm⁻¹; ¹H NMR (CDCl₃) δ 3.60(d, J=10.2 Hz, 1H), 3.55 (d, J=9.7 Hz, 1H), 3.24 (s, 6H), 3.12 (t, J=8.2Hz, 1H), 2.45-0.64 (m), 0.70 (s, 3H); ¹³C NMR (CDCl₃) δ 212.1, 90.4,71.8, 59.0, 57.6, 54.0, 51.2, 46.3, 44.8, 42.8, 38.8, 38.7, 38.0, 35.5,34.3, 31.0, 28.3, 27.5, 23.1, 21.8, 11.5. Anal. Calcd for C₂₁H₃₄O₃: C,75.41; H, 10.25. Found: C, 75.37; H, 10.13.

(5α,17β)-17,19-Dimethoxyandrostan-3-ol (8, MQ-89

To a solution of steroid 7 (200 mg, 0.60 mmol) in THF (10 mL) was addedK-selectride® (1.0 mmol, 1.0 M in THF, 1.0 mL) at −78° C. After 2 h, 3 NNaOH (10 mL) and H₂O₂ (5 mL) were added at −78° C. and the reaction wasallowed to warm up to room temperature for 1 h. The product wasextracted into EtOAc (100 mL×2) and washed with brine. The organiclayers were combined and dried over MgSO₄, filtered, and concentrated.The residue was purified by column chromatography (silica gel elutedwith 20% EtOAc in hexanes) to give steroid 8 (172 mg, 86%): mp 62-64°C.; [α]_(D) ²⁰=1.1 (c=0.26, CHCl₃); ν_(m) 3382, 1447 cm⁻¹; ¹H NMR(CDCl₃) δ 4.10-4.05 (m, 1H), 3.50 (d, J=10.2 Hz, 1H), 3.42 (d, J=9.8 Hz,1H), 3.33 (s, 3H), 3.29 (s, 3H), 3.23 (t, J=8.2, 1H), 2.01-0.80 (m),0.76 (s, 3H); ¹³C NMR (CDCl₃) δ 90.9, 71.1, 66.4, 59.1, 57.8, 54.7,51.6, 43.0, 39.6, 39.3, 38.5, 36.2, 35.8, 31.5, 29.5, 28.1, 27.7, 27.0,23.3, 21.7, 11.7. Anal. Calcd for C₂₁H₃₆O₃: C, 74.95; H, 10.78. Found:C, 75.19; H, 10.79.

(5α)-19-Methoxyandrostane-3,17-dione, cyclic bis-(1,2-ethanediyl acetal)(9)

A mixture of the known (5α)-19-hydroxyandrostane-3,17-dione, cyclicbis-(1,2-ethanediyl) acetal (430 mg, 1.1 mmol), NaH (200 mg, 5 mmol) andTHF (10 mL) was heated at reflux for 2 h under N₂. The reaction mixturewas cooled to room temperature, and methyl iodide (2 mL, 32 mmol) wasadded and the mixture was stirred at room temperature for 13 h. Thereaction mixture was cooled to 0° C. and excess NaH was carefullyquenched by adding MeOH (2 mL). Water (100 mL) was added and the productwas extracted into EtOAc (80 mL×3). The combined organic extracts werewashed with brine, dried and concentrated to give a colorless liquid.The crude product was purified by flash column chromatography (silicagel eluted with 15-20% EtOAc in hexanes) to give the product as acolorless liquid (440 mg, 99%): IR υ_(max) 2923, 1457, 1378, 1306, 1210cm⁻¹; ¹H NMR δ 3.89 (s, 4H), 3.87-3.82 (m, 4H), 3.47 (d, J=10.0 Hz, 1H),3.39 (d, J=9.9 Hz, 1H), 3.25 (s, 3H), 2.20-0.85 (m), 0.82 (s, 3H); ¹³CNMR 119.3, 109.2, 71.0, 65.0, 64.5, 64.0, 59.0, 54.0, 50.4, 46.0, 43.8,38.9, 38.4, 36.2, 34.1, 31.5, 31.1, 31.0 (2×C), 29.6, 28.1, 22.6, 21.7,14.4. Anal. Calcd for: C₂₄H₃₈O₅: C, 70.90%; H, 9.42%. Found: C, 71.17%;H, 9.53%.

(5α)-19-Methoxyandrostane-3,17-dione (10)

A mixture of steroid 9 (400 mg, 0.98 mmol), PTSA (100 mg), acetone (8mL) and water (0.5 mL) was stirred at room temperature for 14 h. Thereaction was neutralized with aqueous NaHCO₃ and the acetone was removedunder reduced pressure. Water (80 mL) was added and the product wasextracted into EtOAc (60 mL×3). The combined EtOAc extracts were driedand concentrated to give a white solid which was purified by flashcolumn chromatography (silica gel eluted with 20-30% EtOAc in hexanes)to yield product 10 (230 mg, 73%): mp 94-96° C.; IR υ_(max) 2918, 1738,1712, 1452, 1407, 1373, 1270, 1248, 1220, 1202, cm⁻¹; ¹H NMR δ 3.60 (d,J=11.0 Hz, 1H), 3.57 (d, J=11.0 Hz, 1H), 3.26 (s, 3H), 2.50-0.74 (m),0.82 (s, 3H); ¹³C NMR δ 220.5, 211.7, 71.7, 59.0, 53.9, 51.3, 47.6,46.1, 44.7, 38.9, 38.5, 35.6, 35.3, 34.2, 31.5, 30.3, 28.1, 21.5, 21.3,13.7. HRMS Calcd for C₂₀H₃₀O₃: 318.2195. Found: 318.2180.

(3α,5α)-3-Hydroxy-19-methoxyandrostan-17-one (11, KK-125)

A 1 M K-Selectride® solution in THF (2 mL, 2 mmol, 3 eq) was added to acold solution (−78° C.) of steroid 10 (210 mg, 0.66 mmol) in THF (5 mL)and the reaction was stirred at −78° C. for 1.5 h. The reaction wasquenched by adding a few drops of acetone and then allowed to warm toroom temperature. 3 N aqueous NaOH (10 mL) followed by 30% aqueous H₂O₂(10 mL) was added and the reaction was stirred at room temperature for1.5 h. The product was extracted into EtOAc (3×60 mL) and the combinedEtOAc extracts were washed with brine, dried, and concentrated to givean off-white solid which was purified by flash column chromatography(silica gel eluted with 20-40% EtOAc in hexanes). Product 11 (142 mg,67%) had: mp 172-174° C.; IR υ_(max) 3436, 2921, 1738, 1453, 1406, 1372,1248, 1203 cm⁻¹; ¹H NMR δ 4.05 (b s, 1H), 3.48 (d, J=9.9 Hz, 1H), 3.38(d, J=10.2 Hz, 1H), 3.25 (s, 3H), 2.39 (dd, J=19.3, 8.8 Hz, 1H),2.2.10-0.70 (m), 0.84 (s, 3H); ¹³C NMR δ 221.5, 71.1, 66.1, 59.0, 54.6,51.7, 47.8, 39.6, 39.2, 36.0, 35.7, 35.5, 31.8, 30.7, 29.2, 27.9, 27.1,21.6, 21.1, 13.8. Anal. Calcd for C₂₀H₃₂O₃: C, 74.96%; H, 10.06%. Found:C, 74.91%; H, 9.86%.

(3α,5α,17β)-19-Methoxyspiro[androstane-17,2′-oxiran]-3-ol (12, MQ-90).

To a solution of steroid 11 (100 mg, 0.3 mmol) in DMF (10 mL) was addedtrimethylsulfonium iodide (306 mg, 1.5 mmol) and potassium tert-butoxide(168 mg, 1.5 mmol) at room temperature. The reaction was quenched byaqueous NH₄Cl after 2 h. The mixture was extracted with dichloromethane(100 mL×2) and washed with brine. The organic layers were combined anddried over MgSO₄, filtered, and concentrated. The residue was purifiedby column chromatography (silica gel eluted with 25% EtOAc in hexanes)to give steroid 12 (76 mg, 75%): mp 168-170° C.; [α]_(D) ²⁰=−3.1(c=0.16, CHCl₃); ν_(max) 3420, 1445 cm⁻¹; ¹H NMR (CDCl₃) δ 4.10-4.05 (m,1H), 3.51 (d, J=10.2 Hz, 1H), 3.42 (d, J=10.2 Hz, 1H), 3.29 (s, 3H),2.90 (d, J=5.1 Hz, 1H), 2.60 (d, J=5.0 Hz, 1H), 2.00-0.77 (m), 0.89 (s,3H); ¹³C NMR (CDCl₃) δ 71.0, 70.6, 66.4, 59.1, 54.6, 53.6, 53.1, 40.2,39.6, 39.3, 36.2, 36.1, 34.3, 31.4, 29.4, 29.0, 28.1, 27.1, 23.5, 21.4,14.4. Anal. Calcd for C₂₁H₃₄O₃: C, 75.41; H, 10.25. Found: C, 75.44; H,9.98.

(3α,5α)-19-Methoxy-3-(methoxymethoxy)-androstan-17-one (13)

To a solution of steroid 11 (800 mg, 2.5 mmol) in DCM (20 mL) was addedchloromethyl methyl ether (302 mg, 3.75 mmol) andN,N-diisopropylethylamine (774 mg, 6 mmol) at room temperature. Themixture was quenched by water after 16 h and extracted with EtOAc (100mL×2) and washed with brine. The organic layers were dried over withMgSO₄, filtered, and concentrated. The residue was purified by columnchromatography (silica gel eluted with 25% EtOAc in hexanes) to giveproduct 13 as an oil (900 mg, 100%): IR ν_(max) 2921, 1740 cm⁻¹; ¹H NMR(CDCl₃) δ 4.65 (q, J=6.6, 10.9, 1H), 3.86-3.84 (m, 1H), 3.52 (d, J=10.2Hz, 1H), 3.43 (d, J=9.8 Hz, 1H), 3.35 (s, 3H), 3.28 (s, 3H), 2.44-0.83(m), 0.86 (s, 3H); ¹³C NMR (CDCl₃) δ 221.4, 94.5, 71.3, 71.2, 59.1,55.1, 54.6, 51.7, 47.9, 39.9, 39.4, 35.8, 35.5, 34.0, 31.9, 30.8, 28.0,27.7, 26.5, 21.7, 21.2, 13.9.

(3α,5α)-19-Methoxy-3-(methoxymethoxy)-androst-16-ene-17-carbonitrile(14)

To a solution of steroid 13 (800 mg, 2.5 mmol) in THF (20 mL) was addedpotassium bis(trimethylsilyl)amide (3.0 mmol, 0.5 M in toluene, 6.0 mL)at −78° C. After 30 min, N-phenyltrifluoromethanesulfonimide (1.07 g,3.0 mmol) in 5 mL of THF was added at −78° C. After 2 h at −78° C., themixture was quenched by water and extracted with EtOAc (50 mL×3). Thecombined organic layers were dried, filtered, and concentrated. Theresidue was purified by flash chromatography (silia gel) to afford theintermediate enol triflate (1.21 g containing an inseparable impurity).To the enol triflate (1.21 g) in a 50 mL round flask was added sodiumcyanide (300 mg, 6.0 mmol), copper (I) iodide (120 mg, 0.6 mmol) andPd(PPh₃)₄ (60 mg) at room temperature. Acetonitrile (25 mL) was addedand the mixture was refluxed for 3 h. The mixture was quenched byaqueous NH₄Cl and extracted with EtOAc (50 mL×3). The combined organiclayers were dried, filtered, and concentrated. The residue was purifiedby flash column chromatography (silica gel eluted with 10% EtOAc inhexanes) to afford product 14 as an oil (886 mg containing aninseparable impurity): ¹H NMR (CDCl₃) δ 6.54-6.53 (m, 1H), 4.62 (q,J=7.0, 9.8 Hz, 2H), 3.80-3.70 (m, 1H), 3.47 (d, J=9.8 Hz, 1H), 3.39 (d,J=10.2 Hz, 1H), 3.30 (s, 3H), 3.23 (s, 3H), 2.29-0.82 (m), 0.85 (s, 3H);¹³C NMR (CDCl₃) δ 147.7, 127.3, 116.0, 94.4, 71.5, 71.3, 59.1, 56.2,55.0, 54.8, 48.4, 39.9, 39.5, 34.3, 34.2, 33.8, 32.8, 31.6, 27.9, 27.4,26.4, 21.5, 16.3.

(3α,5α)-3-Hydroxy-19-methoxyandrost-16-ene-17-carbonitrile (15, MQ-91)

To steroid 14 containing an inseparable impurity (886 mg) in methanol(20 mL) was added 6 N HCl (15 ml) at room temperature. After 14 h, themixture was extracted with dichloromethane (50 mL×2). The combinedorganic layers were dried, filtered, and concentrated. The residue waspurified by flash column chromatography (silica gel eluted with 30%EtOAc in hexanes) to afford product 15 (480 mg, 58% yield from steroid13): mp 167-169° C.; [α]_(D) ²⁰=11.1 (c=0.18, CHCl₃); IR ν_(max) 3337,2212 cm⁻¹; ¹H NMR (CDCl₃) δ 6.59-6.55 (m, 1H), 4.08-4.05 (m, 1H), 3.53(d, J=10.1 Hz, 1H), 3.43 (d, J=10.1 Hz, 1H), 3.28 (s, 3H), 2.37-0.89(m), 0.91 (s, 3H); ¹³C NMR (CDCl₃) δ 147.2, 127.5, 115.9, 71.1, 66.1,59.1, 56.2, 54.8, 48.3, 39.7, 39.3, 36.0, 34.4, 34.3, 32.8, 31.6, 29.3,28.0, 26.9, 21.5, 16.3. Anal. Calcd for C₂₁H₃₁NO₂: C, 76.55; H, 9.48, N,4.25. Found: C, 76.59; H, 9.32; N, 4.06.

(3α,5α,17β)-3-Hydroxy-19-methoxyandrostane-17-carbonitrile (16, MQ-92)

To a solution of steroid 15 (430 mg, 1.3 mmol) in EtOAc (30 mL) wasadded Pd/C (10%, 100 mg). A hydrogenation was carried out under 7 atm H₂at room temperature for 3 h. The mixture was filtered through Celite andwashed with EtOAc (100 mL). Solvents were removed and the residue waspurified by flash column chromatography (silica gel eluted with 10%EtOAc in hexanes) to afford product 16 (415 mg, 96%): mp 146-148° C.;[α]_(D) ²⁰=42.1 (c=0.29, CHCl₃); ν_(max) 3412, 2235 cm⁻¹; ¹H NMR (CDCl₃)δ 4.08-4.05 (m, 1H), 3.49 (d, J=9.8 Hz, 1H), 3.39 (d, J=9.8 Hz, 1H),3.29 (s, 3H), 2.25 (t, J=8.8 Hz, 1H), 2.10-0.79 (m), 0.92 (s, 3H); ¹³CNMR (CDCl₃) δ 121.4, 70.9, 66.3, 59.1, 54.7, 54.3, 44.5, 40.2, 39.5,39.2, 37.5, 36.4, 36.1, 31.9, 29.4, 28.0, 27.1, 26.5, 24.5, 21.6, 14.4.Anal. Calcd for C₂₁H₃₃NO₂: C, 76.09; H, 10.03, N, 4.23. Found: C, 76.16;H, 9.90; N, 4.05.

(3α,5α)-3-Hydroxy-19-methoxypregnan-20-one (17, MQ-93)

To a solution of steroid 16 (360 mg, 1.09 mmol) in THF (20 mL) was addedmethyl magnesiumbromide (3.0 M, 2 mL, 6.0 mmol) at room temperature. Themixture was then refluxed for 16 h and subsequently allowed to cool toroom temperature and quenched by 6 N HCl addition. The product wasextracted into dichloromethane (50 mL×3). The combined organic layerswere dried, filtered, and concentrated. The ¹H NMR of the crude product(300 mg, 79%) showed the 17β (steroid 17) and 17α diastereomer in theratio of 8 to 1, respectively. The crude product was purified by flashcolumn chromatography (silica gel eluted with 25% EtOAc in hexanes) toafford pure product 17 (135 mg) pure: mp 160-162° C.; [α]_(D) ²⁰=41.7(c=0.31, CHCl₃); IR ν_(max) 3407, 1703 cm⁻¹; ¹H NMR (CDCl₃) δ 4.07-4.05(m, 1H), 3.47 (d, J=9.8 Hz, 1H), 3.40 (d, J=10.2 Hz, 1H), 3.26 (s, 3H),2.50 (t, J=9.4 Hz, 1H), 2.17-0.78 (m), 2.08 (s, 3H), 0.59 (s, 3H); ¹³CNMR (CDCl₃) δ 209.8, 70.9, 66.3, 63.8, 59.0, 56.9, 54.4, 44.3, 39.5,39.4, 39.2, 36.1, 35.9, 31.8, 31.4, 29.3, 28.1, 26.9, 24.3, 22.6, 22.0,13.5. Anal. Calcd for C₂₂H₃₆O₃: C, 75.82; H, 10.41; found: C, 75.71; H,10.29.

(3α,5α)-3-(Acetyloxy)-19-methoxypregnan-20-one (18)

To a solution of steroid 17 (100 mg, 0.29 mmol) in pyridine (5 mL) wasadded acetic anhydride (51 mg, 0.5 mmol) and DMAP (5 mg) at roomtemperature. The reaction mixture was quenched by water after 2 h andextracted with EtOAc (50 mL×2). The combined organic layers were driedwith MgSO₄, filtered, and concentrated. The residue was purified byflash column chromatography (silica gel eluted with 20% EtOAc inhexanes) to give product 18 as an oil (112 mg, 100%): ¹H NMR (CDCl₃) δ5.01-4.98 (m, 1H), 3.46 (d, J=9.8 Hz, 1H), 3.37 (d, J=9.8 Hz, 1H), 3.23(s, 3H), 2.47 (t, J=9.0 Hz, 1H), 2.22-0.79 (m), 2.06 (s, 3H), 2.00 (s,3H), 0.57 (s, 3H); ¹³C NMR (CDCl₃) δ 209.4, 170.5, 70.9, 69.9, 63.7,59.0, 56.8, 54.2, 44.2, 40.1, 39.3, 39.1, 35.8, 33.1, 31.7, 31.4, 27.8,27.7, 26.3, 24.2, 22.6, 21.9, 21.4, 13.4.

(3α,5α)-3,21-bis(Acetyloxy)-19-methoxylpregnan-20-one (19)

To a solution of steroid 18 (112 mg, 0.29 mmol) in benzene (10 mL) andmethanol (0.5 mL) was added lead tetraacetate (513 mg, 1.15 mmol) andboron trifluoride ether complex (1 mL) at room temperature. After 3 h,water was added and the product extracted into EtOAc (50 mL×2). Thecombined organic layers were dried over with MgSO₄, filtered, andconcentrated. The residue was purified by flash column chromatography(silica gel eluted with 25% EtOAc in hexanes) to give product 19 as afoam (82 mg, 63%): ¹H NMR (CDCl₃) δ 5.03-5.01 (m, 1H), 4.70 (d, J=16.8Hz, 1H), 4.53 (d, J=16.8 Hz, 1H), 3.47 (d, J=10.2 Hz, 1H), 3.34 (d,J=10.2 Hz, 1H), 3.25 (s, 3H), 2.47 (t, J=9.0 Hz, 1H), 2.20-0.80 (m),2.14 (s, 3H), 2.03 (s, 3H), 0.65 (s, 3H); ¹³C NMR (CDCl₃) δ 203.8,170.6, 170.2, 70.9, 69.9, 69.1, 59.4, 59.0, 57.1, 54.2, 45.0, 40.1,39.2, 39.1, 35.9, 33.2, 31.8, 27.9, 27.8, 26.4, 24.4, 22.7, 22.0, 21.5,20.4, 13.3.

(3α,5α)-3,21-Dihydroxy-19-methoxypregnan-20-one (20, MQ-98)

To a solution of steroid 19 (82 mg, 0.18 mmol) in methanol was addedpotassium bicarbonate (280 mg, 2.0 mmol) at room temperature. Themixture was refluxed for 5 h. Water was added and the product wasextracted into EtOAc (50 mL×2). The combined organic layers were driedover with MgSO₄, filtered, and concentrated. The residue was purified byflash column chromatography (silica gel eluted with 25% EtOAc inhexanes) to give product 20 (22 mg, 37%): mp 88-90° C.; [α]_(D) ²⁰=50.0(c=0.13, CHCl₃); IR ν_(max) 3415, 1708 cm⁻¹; ¹H NMR (CDCl₃) δ 4.20-4.10(m, 3H), 3.49 (d, J=9.8 Hz, 1H), 3.42 (d, J=9.8 Hz, 1H), 3.28 (d, J=1.9Hz, 3H), 2.47 (t, J=8.6 Hz, 1H), 2.22-0.80 (m), 0.65 (J=1.2 Hz, 3H); ¹³CNMR (CDCl₃) δ 210.4, 70.9, 69.4, 66.4, 59.4, 59.1, 57.1, 54.3, 45.1,39.5, 39.2, 39.1, 36.1, 36.0, 31.9, 29.4, 28.1, 27.0, 24.5, 22.9, 22.0,13.6. Anal. Calcd for C₂₂H₃₆O₄: C, 72.49; H, 9.95; found: C, 72.77; H,10.10.

19-Hydroxyandrost-5-ene-3,17-dione, 3-cyclic 1,2-ethandiyl acetal (21)

To a solution of the known 19-hydroxyandrost-4-ene-3,17-dione (1.0 g,3.3 mmol) in benzene (100 mL) was added ethylene glycol (267 mg, 4.3mmol) and PPTS (100 mg). The mixture was refluxed in a flask equippedwith a Dean-Stark trap. After 4 h, the mixture was cooled down to roomtemperature and solvent was removed by reduced pressure. The residue waspurified by flash column chromatography (silica gel eluted with 15%EtOAc in hexanes) to afford the known19-hydroxyandrost-5-ene-3,17-dione, 3,17-bis(cyclic 1,2-ethandiylacetal) (260 mg, 20%) and product 21 (450 mg, 39%): mp 190-192° C.; IRν_(max) 3468, 1735 cm⁻¹; ¹H NMR (CDCl₃) δ 5.67-5.65 (m, 1H), 3.93-3.3.77(m, 5H), 3.58-3.55 (m, 1H), 2.48-0.96 (m), 0.87 (s, 3H); ¹³C NMR (CDCl₃)δ 221.2, 135.4, 126.4, 109.0, 64.4, 64.2, 62.5, 52.4, 50.0, 47.8, 41.8,41.6, 35.7, 32.8, 32.4, 31.6, 31.3, 30.0, 21.7, 20.9, 13.9.

(17β)-17,19-Dihydroxyandrost-5-en-3-one, 3-cyclic 1,2-ethandiyl acetal(22)

To a solution of steroid 21 (450 mg, 1.29 mmol) in ethanol (50 mL) wasadded sodium borohydride (152 mg, 4 mmol) at room temperature. After 3h, aqueous NH₄Cl was added and the product extracted into EtOAc (50mL×3). The combined organic layers were dried with MgSO₄, filtered, andconcentrated. The residue was purified by flash column chromatography(silica gel eluted with 35% EtOAc in hexanes) to give product 22 (374mg, 83%): mp 208-210° C.; IR ν_(max) 3440 cm⁻¹; ¹H NMR (CDCl₃) δ5.74-5.70 (m, 1H), 4.00-3.92 (m, 4H), 3.85 (d, J=11.4 Hz, 1H), 3.70-3.62(m, 2H), 2.22-0.84 (m), 0.82 (s, 3H); ¹³C NMR (CDCl₃) δ 135.1, 127.3,109.1, 81.8, 64.5, 64.3, 62.6, 52.1, 50.0, 42.9, 41.9, 41.8, 36.8, 33.4,32.4, 31.4, 30.6, 30.5, 23.3, 21.3, 11.3.

(17β)-17,19-Dimethoxyandrost-5-en-3-one, 3-cyclic 1,2-ethandiyl acetal(23)

To a solution of steroid 22 (374 mg, 0.72 mmol) in THF (30 mL) was addedsodium hydride (400 mg, 60% in mineral oil, 6.0 mmol). After addition,the mixture was refluxed for 1 h, iodomethane (2.13 g, 15 mmol) wasadded and reflux was continued for 3 h. After allowing cooling to roomtemperature, water was added and the product was extracted into EtOAc(100 mL×3). The combined organic layers were dried with MgSO₄, filtered,and concentrated. The residue was purified by flash columnchromatography (silica gel eluted with 20% EtOAc in hexanes) to giveproduct 22 (402 mg, 100%): mp 97-99° C.; IR ν_(max) 2918, 1450, 1105cm⁻¹; ¹H NMR (CDCl₃) δ 5.52-5.50 (m, 1H), 3.95-3.83 (m, 4H), 3.51 (d,J=9.8 Hz, 1H), 3.27 (s, 3H), 3.27 (d, J=11.4 Hz, 1H), 3.24 (s, 3H), 3.15(t, J=7.8 Hz, 1H), 2.56-0.78 (m), 0.73 (s, 3H); ¹³C NMR (CDCl₃) δ 136.1,124.8, 109.1, 90.6, 73.6, 64.2, 64.0, 58.8, 57.6, 51.9, 49.9, 42.6,42.0, 40.6, 38.0, 32.6, 32.5, 31.3, 30.8, 27.5, 23.1, 21.2, 11.3.

(17β)-17,19-Dimethoxyandrost-4-en-3-one (24, MQ-99)

To a solution of steroid 23 (402 mg, 1.07 mmol) in THF (20 mL) was added3 N HCl (10 mL at room temperature. The mixture was stirred for 2 h andthe product extracted into dichloromethane (50 mL×2). The combinedorganic layers were dried with MgSO₄, filtered, and concentrated. Theresidue was purified by flash column chromatography (silica gel elutedwith 25% EtOAc in hexanes) to give product 24 (355 mg, 100%): IR ν_(max)1671 cm⁻¹; mp 93-95° C.; [α]_(D) ²⁰=124.7 (c=0.32, CHCl₃); ¹H NMR(CDCl₃) δ 5.80 (d, J=0.7 Hz, 1H), 3.68 (d, J=9.3 Hz, 1H), 3.51 (d, J=9.4Hz, 1H), 3.28 (s, 3H), 3.25 (s, 3H), 3.18 (t, J=8.2 Hz, 1H), 2.27-0.90(m), 0.74 (s, 3H); ¹³C NMR (CDCl₃) δ 199.9, 167.5, 125.5, 90.2, 76.0,59.2, 57.7, 54.1, 50.9, 42.8, 42.7, 37.8, 35.9, 34.8, 33.6, 33.4, 31.6,27.4, 23.0, 21.2, 11.5. Anal. Calcd for C₂₁H₃₂NO₃: C, 75.86, H, 9.70.Found: C, 76.00, H, 9.98.

(3α,17β)-17,19-Dimethoxyandrost-5-en-3-61 (25, MQ-101) and(3β,17β)-17,19-Dimethoxyandrost-5-en-3-61 (26, MQ-100)

To a solution of steroid 24 (355 mg, 1.07 mmol) in acetic anhydride (10mL) was added sodium iodide (600 mg, 4 mmol) and TMSCl (435 mg, 4 mmol)at 0° C. After addition, the mixture was allowed to warm up to roomtemperature for 1 h. Thin layer chromatography showed no remainingstarting material. Aqueous NaHCO₃ was added and the product extractedinto EtOAc (50 mL×3). The combined organic layers were dried with MgSO₄,filtered, and concentrated. The residue was dissolved in ethanol (20 mL)and NaBH₄ (200 mg) was added. After 16 h, aqueous NH₄Cl was added andthe product extracted into EtOAc (50 mL×3). The combined organic layerswere dried with MgSO₄, filtered, and concentrated. The residue waspurified by flash column chromatography (silica gel eluted with 30%EtOAc in hexanes) to give product 25 (30 mg, 8%), and product 26 (248mg, 69%).

Product 25 had: mp 132-134° C.; [α]_(D) ²⁰=−64.0 (c=0.10, CHCl₃); IRν_(max) 3337, 1446 cm⁻¹; ¹H NMR (CDCl₃) δ 5.67-5.65 (m, 1H), 4.05-4.00(m, 1H), 3.60 (d, J=9.8 Hz, 1H), 3.35 (s, 3H), 3.31 (s, 3H), 3.28 (d,J=9.8 Hz, 1H), 3.25 (t, J=8.2 Hz, 1H), 2.64-2.60 (m, 1H), 2.17-0.85 (m),0.80 (s, 3H); ¹³C NMR (CDCl₃) δ 134.8, 126.9, 90.8, 73.7, 66.9, 59.1,57.9, 52.1, 50.8, 42.8, 41.5, 40.0, 38.2, 32.9, 31.1, 30.2, 29.3, 27.7,23.3, 21.1, 11.5. Anal. Calcd for C₂₁H₃₄O₃: C, 75.41, H, 10.25. Found:C, 75.31, H, 10.41.

Product 26 had: mp 160-162° C.; [α]_(D) ²⁰=δ 76.7 (c=0.45, CHCl₃); IRν_(max) 3408 cm⁻¹; ¹H NMR (CDCl₃) δ 5.53-5.50 (m, 1H), 3.54 (d, J=9.7Hz, 1H), 3.51-3.44 (m, 1H), 3.28 (s, 3H), 3.24 (s, 3H), 3.22 (d, J=9.7Hz, 1H), 3.18 (t, J=8.2 Hz, 1H), 2.65 (s, br, 1H), 2.32-0.76 (m), 0.73(s, 3H); ¹³C NMR (CDCl₃) δ 136.9, 124.4, 90.7, 73.8, 71.1, 58.8, 57.7,51.9, 50.4, 42.6, 42.2, 40.5, 38.0, 33.6, 32.6, 31.6, 30.7, 27.5, 23.1,21.2, 11.3. Anal. Calcd for C₂₁H₃₄O₃: C, 75.41, H, 10.25. Found: C,75.51, H, 10.30.

(3α,5α)-3-[[(Dimethylethyl)dimethylsilyl]oxy]-19-methkoxyandrostan-17on(27)

To a solution of steroid 11 (150 mg, 0.47 mmol) in DMF (5 ml) was addedtert-butyldimethylsilyl chloride (150 mg, 1.0 mmol) and imidazole (132mg, 2.0 mmol) at room temperature. After 16 h, water was added and theproduct extracted into EtOAc (50 mL×2). The combined organic layers weredried with MgSO₄, filtered and removed. The residue was purified byflash column chromatography (silica gel eluted with 10% EtOAc inhexanes) to afford product 27 as an oil (198 mg, 99%): ¹H NMR (CDCl₃) δ4.00-3.95 (m, 1H), 3.51 (d, J=9.7 Hz, 1H), 3.40 (d, J=9.7 Hz, 1H), 3.27(s, 3H), 2.44-0.80 (m), 0.89 (s, 3H), 0.87 (s, 9H), 0.00 (d, J=1.6 Hz,6H); ¹³C NMR (CDCl₃) δ 221.6, 71.3, 66.6, 59.1, 54.7, 51.7, 47.9, 39.6,39.2, 37.0, 35.8, 35.5, 31.8, 30.9, 29.9. 28.1, 27.2, 25.8 (3×C), 25.6,21.7, 21.2, 13.9, −4.90, −4.92.

(3α,5α)-3-[[(Dimethylethyl)dimethylsilyl]oxy]-19-methoxyandrostan-17-one,oxime (28)

To a solution of the steroid 27 (195 mg, 0.45 mmol) in pyridine (10 mL)was added hydroxyamine hydrochloride (140 mg, 2.0 mmol) at roomtemperature. After 14 h, water was added and the product extracted intoEtOAc (50 mL×2). The combined organic layers were dried with MgSO₄,filtered and removed. The residue was purified by flash columnchromatography (silica gel eluted with 20% EtOAc in hexanes) to affordproduct 28 as an oil (202 mg, 100%): ¹H NMR (CDCl₃) δ 9.05 (s, br, 1H),4.00-3.95 (m, 1H), 3.50 (d, J=9.8 Hz, 1H), 3.41 (d, J=9.8 Hz, 1H), 3.27(s, 3H), 2.50-0.82 (m), 0.91 (s, 3H), 0.88 (s, 9H), 0.11 (d, J=1.9 Hz,6H); ¹³C NMR (CDCl₃) δ 171.1, 71.4, 66.7, 59.1, 54.7, 54.1, 44.2, 39.6,39.2, 37.1, 35.2, 34.3, 31.5, 30.0, 28.2, 27.1, 25.8 (3×C), 25.0, 23.1,21.5, 18.1, 17.2, −4.85, −4.89.

(3α,5α,17β)-19-methoxy-17-nitroandrostan-3-ol (29, MQ-97)

To a solution of NBS (231 mg, 1.3 mmol) in dioxane (4 mL) was addedaqueous KHCO₃ (260 mg, 2.6 mmol, 4 mL) at room temperature. The mixturewas stirred for 30 min at room temperature, then the oxime (202 mg, 0.45mmol) in dioxane (10 ml) was added. The reaction was stirred in an openflask for 14 h at room temperature. NaBH₄ was added (200 mg) in 5portions and the reaction was stirred for 3 h at room temperature. 6 NHCl (10 ml) was slowly added and stirring at room temperature wascontinued for 1 h. The product was extracted into dichloromethane (50mL×2). The combined organic layers were dried with MgSO₄, filtered, andremoved. The residue was purified by flash column chromatography (silicagel eluted with 30% EtOAc in hexanes) to afford product 29 (79 mg, 50%):mp 52-54° C.; [α]_(D) ²⁰=25.8 (c=0.21, CHCl₃); IR ν_(max) 3307, 1541,1370 cm⁻¹; ¹H NMR (CDCl₃) δ 4.38 (t, J=8.6 Hz, 1H), 4.10-4.05 (m, 1H),3.49 (d, J=9.8 Hz, 1H), 3.41 (d, J=9.8 Hz, 1H), 3.27 (s, 3H), 2.55-0.79(m), 0.74 (s, 3H); ¹³C NMR (CDCl₃) δ 94.5, 71.0, 66.3, 59.1, 54.2, 53.4,46.0, 39.5, 39.1, 37.6, 36.0, 31.5, 29.3, 28.0, 27.1, 24.7, 23.6, 21.7,12.2. Anal. Calcd for C₂₀H₃₃NO₄: C, 68.34, H, 9.46. Found: C, 68.40, H,9.45.

(3α,5β)-3-Hydroxy-19-methoxyandrostan-17-one (30, MQ-94)

To a solution of steroid 10 (295 mg, 0.93 mmol) in THF (20 mL) was addedlithium aluminum tri-tert-butoxide hydride (2.0 mmol, 1.0 M in THF, 2.0mL) at −40° C. After 2 h, the mixture was quenched by 3 N HCl at −40°C., the reaction was allowed to warm up to room temperature for 1 h. Theproduct was extracted into dichloromethane (100 mL×2) and washed withbrine. The combined organic extracts were dried with MgSO₄, filtered,and concentrated. The residue was purified by flash columnchromatography (silica gel eluted with 30% EtOAc in hexanes) to giveproduct 30 (239 mg, 81%): mp 208-210° C.; IR ν_(max) 3428, 1737, 1642cm⁻¹; [α]_(D) ²⁰=81.3 (c=0.31, CHCl₃); ¹H NMR (CDCl₃) δ 3.65-3.58 (m,1H), 3.52 (d, J=9.8 Hz, 1H), 3.43 (d, J=9.8 Hz, 1H), 3.27 (s, 3H),2.44-0.65 (m), 0.85 (s, 3H); ¹³C NMR (CDCl₃) δ 221.4, 71.5, 70.8, 59.1,54.6, 51.6, 47.9, 44.9, 39.0, 38.3, 35.8, 35.5, 32.0, 31.8, 31.6, 30.8,28.0, 21.7, 21.6, 13.8. Anal. Calcd for C₂₀H₃₂O₃: C, 74.96; H, 10.06.Found: C, 75.10; H, 9.95.

(3β,5α,17β)-17,19-Dimethoxyandrostan-3-61 (31, MQ-96)

To a solution of steroid 7 (65 mg, 0.20 mmol) in THF (10 mL) was addedlithium aluminum tri-tert-butoxide hydride (1.0 mmol, 1.0 M in THF, 1.0mL) at −40° C. After 2 h, the mixture was quenched by 3 N HCl at −40° C.and the reaction was allowed to warm up to room temperature for 1 h. Theproduct was extracted into dichloromethane (50 mL×2) and washed withbrine. The combined organic layers were dried with MgSO₄, filtered, andconcentrated. The residue was purified by flash column chromatography(silica gel eluted with 25% EtOAc in hexanes) to give product 31 (55 mg,85%): mp 164-166° C.; IR ν_(max) 3370 cm⁻¹; [α]_(D) ²⁰=1.0 (c=0.10,CHCl₃); ¹H NMR (CDCl₃) δ 3.65-3.57 (m, 1H), 3.51 (d, J=10.2 Hz, 1H),3.43 (d, J=10.2 Hz, 1H), 3.33 (s, 3H), 3.29 (s, 3H), 3.22 (t, J=8.2 Hz,1H), 2.24-0.60 (m), 0.76 (s, 3H); ¹³C NMR (CDCl₃) δ 90.8, 71.5, 71.0,59.1, 57.8, 54.7, 51.5, 45.0, 43.0, 38.9, 38.5, 38.4, 35.8, 32.0, 31.8,31.6, 28.2, 27.7, 23.2, 22.2, 11.7. Anal. Calcd for C₂₁H₃₆O₃: C, 74.95;H, 10.78. Found: C, 74.91; H, 10.82.

B. [³⁵S]-TBPS Displacement

The IC₅₀ values for non-competitive displacers of [³⁵S]-TBPS from thepicrotoxin binding site on GABA_(A) receptors are reported in Table 1.

TABLE 1 Inhibition of [³⁵S]-TBPS Binding by Example Compounds^(a)Compound IC₅₀ (nM) n_(Hill) 7, MQ-88 (Prodrug)  8,700 ± 1,500 1.27 ±0.15 8, MQ-89 56 ± 2 1.05 ± 0.03 10 (Prodrug) — — 11, KK-125  4,300 ±1,200 0.95 ± 0.15 12, MQ-90 79 ± 4 1.06 ± 0.04 15, MQ-91 118 ± 13 1.01 ±0.10 16, MQ-92 63 ± 7 1.24 ± 0.14 17, MQ-93 47 ± 4 1.17 ± 0.09 20, MQ-98345 ± 61 0.88 ± 0.12 24, MQ-99 (Prodrug)  14,500 ± 10,700 1.24 ± 0.4725, MQ-101 583 ± 71 0.94 ± 0.09 26, MQ-100 17,800 ± 8,400 1.19 ± 0.24(Prodrug) 29, MQ-97 37 ± 4 0.88 ± 0.08 30, MQ-94 (Prodrug) >30,000 — 31,MQ-96 (Prodrug)  7,800 ± 2,900 1.27 ± 0.33 ^(a)Results presented arefrom duplicate experiments performed in triplicate. Error limits arecalculated as standard error of the mean. Methods used are known in theart (see Jiang, X., et al., Neurosteroid analogues. 9. Conformationallyconstrained pregnanes: structure-activity studies of13,24-cyclo-18,21-dinorcholane analogues of the GABA modulatory andanesthetic steroids (3α,5α)- and (3α,5α)-3-hydroxypregnan-20-one. J.Med. Chem., 46: 5334-48 (2003) - the contents of which are herebyincorporated by reference in their entirety).

C. Electrophysiology Results

The compounds of the present disclosure were evaluated for the abilityto potentiate chloride currents mediated by 2 μM GABA at rat α₁β₂γ_(2L)type GABA_(A) receptors expressed in Xenopus laevis oocytes and theresults are shown in Table 2.

TABLE 2 Modulation of Rat α₁β₂γ_(2L) GABA_(A) Receptor Function byExample Compounds oocyte electrophysiology^(a) Compound 0.1 μM 1 μM 10μM (gating) 10 μM 7, MQ-88 1.00 ± 0   0.85 ± 0.01 1.07 ± 0.02 0.04 ±0.03 (Prodrug) 8, MQ-89 1.65 ± 0.08 7.63 ± 0.77 20.9 ± 2.73 0.22 ± 0.0110 (Prodrug) — — — — 11, KK-125 0.71 ± 0.02 0.76 ± 0.07 2.17 ± 0.12   0± 0.07 12, MQ-90 1.24 ± 0.05 7.40 ± 1.43 18.7 ± 6.19 0.14 ± 0.04 15,MQ-91 1.27 ± 0.13 5.34 ± 0.86 25.6 ± 3.23 0.10 ± 0.09 16, MQ-92 1.52 ±0.02 9.79 ± 0.53 25.7 ± 2.11 0.25 ± 0.11 17, MQ-93 2.15 ± 0.19 12.8 ±1.74 33.8 ± 5.44 0.23 ± 0.07 20, MQ-98 0.98 ± 0.01 2.76 ± 0.27 19.0 ±2.31 0.09 ± 0.05 24, MQ-99 0.88 ± 0.08 0.63 ± 0.06 1.06 ± 0.17 0.11 ±0.17 (Prodrug) 25, MQ-101 0.94 ± 0.07 1.97 ± 0.08 15.7 ± 0.90 0.08 ±0.07 26, MQ-100 0.83 ± 0.03 0.76 ± 0.02 0.78 ± 0.02 0.02 ± 0.02(Prodrug) 29, MQ-97 2.07 ± 0.09 15.7 ± 1.45 26.6 ± 4.34 0.11 ± 0.01 30,MQ-94 0.90 ± 0.02 0.88 ± 0.01 0.84 ± 0.02 0.03 0.02 (Prodrug) 31, MQ-960.91 ± 0.02 0.97 ± 0.05 1.10 ± 0.05 0.02 ± 0   (Prodrug) ^(a)The GABAconcentration used for the control response was 2 μM. Each compound wasevaluated on at least four different oocytes at the concentrationsindicated, and the results reported are the ratio of currents measuredin the presence/absence of added compound. Gating represents directcurrent gated by 10 μM compound in the absence of GABA, and this currentis reported as the ratio of compound only current/2 μM GABA current.Error limits are calculated as standard error of the mean (N ≧4).Methods used are known in the art (see Jiang, X., et al.).

D. Tadpole Loss of Righting and Swimming

Table 3 discloses the anesthetic effects of the compounds of the presentdisclosure. In particular, the anesthetic effect of the compounds of thepresent disclosure on Loss of Righting Reflex (LRR) and Loss of SwimmingReflex (LSR).

TABLE 3 Effects of Examples on Tadpole Righting and SwimmingReflexes^(a) Tadpole Tadpole Tadpole LRR LRR LSR Tadpole LSR CompoundEC₅₀ (μM) n_(Hill) EC₅₀ (μM) n_(Hill) 7, MQ-88 1.71 ± 0.25 −2.41 ± 0.565.48 ± 0.12  −33.3 ± 0.10 (Prodrug) 8, MQ-89 332 ± 43  −2.32 ± 0.75 1.07± 0.01  −16.1 ± 0.64 10 (Prodrug) — — — — 11, KK-125 7.95 ± 3.29 −1.81 ±0.97 17.3 ± 0.2  −36.2 ± 0.2 12, MQ-90 1.73 ± 0.05 −2.53 ± 0.11 3.54 ±2.33 −17.9 ± 71  15, MQ-91 1.22 ± 0.94 −7.11 ± 28.0 2.71 ± 0   −21.4 ±0.7 16, MQ-92 0.36 ± 0.04 −3.37 ± 1.34 0.99 ± 0.17 −21.7 ± 0.6 17, MQ-930.36 ± 0.04 −2.74 ± 1.12 1.71 ± 0.03 −36.3 ± 0.1 20, MQ-98 3.15 ± 0.50−2.54 ± 1.23 5.48 ± 0.12 −33.3 ± 0.1 24, MQ-99 None — None — (Prodrug)25, MQ-101 3.38 ± 0.38 −2.80 ± 1.13 10.5 ± 0   −21.1 ± 0   26, MQ-100None — None — (Prodrug) 29, MQ-97 0.16 ± 0.01 −1.84 ± 0.11 0.55 ± 0.01−33.3 ± 0.1 30, MQ-94 >10 — None — (Prodrug) 31, MQ-96 7.04 ± 1.98 −1.66± 0.51 16.8 ± 5.9  −3.27 ± 2.5 (Prodrug)

Methods used are known in the art (see Jiang, X., et al.). Error limitsare calculated as standard error of the mean (N=10 or more animals ateach of five or more different concentrations).

General Methods

The compounds discussed in the present disclosure were produced asdiscussed elsewhere throughout this disclosure and by the followingmethods.

Solvents were either used as purchased or dried and purified by standardmethodology. Extraction solvents were dried with anhydrous Na₂SO₄ andafter filtration, removed on a rotary evaporator. Flash chromatographywas performed using silica gel (32-63 μm) purchased from ScientificAdsorbents (Atlanta, Ga.). Melting points were determined on a Koflermicro hot stage and are uncorrected. FT-IR spectra were recorded asfilms on a NaCl plate. NMR spectra were recorded in CDCl₃ at ambienttemperature at 300 MHz (¹H) or 74 MHz (¹³C). Purity was determined byTLC on 250 μm thick Uniplates™ from Analtech (Newark, Del.). All purecompounds (purity >95%) gave a single spot on TLC. Elemental analyseswere performed by M-H-W Laboratories (Phoenix, Ariz.).

EQUIVALENTS AND SCOPE

In view of the above, it will be seen that the several advantages of thedisclosure are achieved and other advantageous results attained. Asvarious changes could be made in the above processes and compositeswithout departing from the scope of the disclosure, it is intended thatall matter contained in the above description and shown in theaccompanying drawings shall be interpreted as illustrative and not in alimiting sense.

When introducing elements of the present disclosure or the variousversions, embodiment(s) or aspects thereof, the articles “a”, “an”,“the” and “said” are intended to mean that there are one or more of theelements. It is also noted that the terms “comprising”, “including”,“having” or “containing” are intended to be open and permits theinclusion of additional elements or steps.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: R₁ is selectedfrom (C₁-C₄ alkyl)-O, spirooxirane, cyano, ═O, nitro, (C₁-C₄ alkyl)C(O),and HO(C₁-C₄ alkyl)C(O); R₂ is ═O, H, or OR_(a), where R_(a) is selectedfrom H, optionally substituted C₁-C₄ alkyl, or optionally substitutedaryl, with the proviso that when R₂ is ═O, R₈ is not present; R₃ is H,optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl; R₄ is independently selected from H and unsubstituted C₁-C₄ alkyl;R₅ is substituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, oroptionally substituted C₂-C₄ alkynyl; R₆ is H, optionally substitutedC₁-C₄ alkyl, or optionally substituted C₁-C₄ alkoxy; R₇ is H, optionallysubstituted C₁-C₄ alkoxy, or an optionally substituted morpholinyl ring;R₈, when present, is H or optionally substituted C₁-C₄ alkyl; - - -denotes an optional, additional C—C bond, resulting in either a C═C bondbetween C₄-C₅ or C₅-C₆, with the proviso that when present, the C₅—Hsubstituent is not present; and, - - - denotes an optional, additionalC—C bond, resulting in a C═C bond between C₁₆-C₁₇, with the proviso thatwhen present, the R₁ is not ═O.
 2. The compound of claim 1, wherein oneor both of R₆ or R₇, when present and other than H, are in the betaconfiguration.
 3. The compound of claim 1 or 2, wherein the R₃ group isselected from the group consisting of H, methyl, and trifluoromethyl. 4.The compound of one of the preceding claims, wherein R₇ is selected fromthe group consisting of H, methoxy, ethoxy, and an optionallysubstituted morpholinyl ring.
 5. The compound of one of the precedingclaims, wherein R₇ is H.
 6. The compound of one of the preceding claims,wherein R₅ is substituted methyl.
 7. The compound of one of thepreceding claims, wherein the C₅—H is in the alpha position.
 8. Thecompound of one of preceding claims 1-6, wherein the C₅—H is in the betaconfiguration and R₅ group is in the beta configuration.
 9. The compoundof one of the preceding claims, wherein R₆ is H.
 10. The compound of oneof the preceding claims, wherein R₂ is ═O, methoxy or H.
 11. Thecompound of one of the preceding claims, wherein R₄ is methyl.
 12. Thecompound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof, wherein R_(b) isoptionally substituted C₁-C₄ alkyl.
 13. The compound of claim 12 whereinR_(b) is methyl.
 14. The compound of claim 12 or 13, wherein R₁ isbeta-methoxy.
 15. The compound of claim 12 or 13, wherein R₁ isbeta-spirooxirane.
 16. The compound of claim 12 or 13, wherein R₁ isbeta-cyano.
 17. The compound of claim 12 or 13, wherein R₁ is ═O. 18.The compound of claim 12 or 13, wherein R₁ is beta-nitro.
 19. Thecompound of claim 12 or 13, wherein R₁ is beta-CH₃C(O)—.
 20. Thecompound of claim 12 or 13, wherein R₁ is beta-HOCH₂C(O)—.
 21. Thecompound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof, wherein R_(b) isoptionally substituted C₁-C₄ alkyl.
 22. The compound of claim 21,wherein R_(b) is methyl.
 23. A pharmaceutically acceptable salt of acompound of one of the preceding claims.
 24. A prodrug of a compound ofone of the preceding claims.
 25. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof; wherein: R₁ is selectedfrom (C₁-C₄ alkyl)-O, spirooxirane, cyano, ═O, nitro, (C₁-C₄ alkyl)C(O),and HO(C₁-C₄ alkyl)C(O); R₂ is ═O, H, or OR_(a), where R_(a) is selectedfrom H, optionally substituted C₁-C₄ alkyl, or optionally substitutedaryl, with the proviso that when R₂ is ═O, R₈ is not present; R_(x) is═O or OR_(d), where R_(d) is H or C(O)R_(e), where R_(e) is optionallysubstituted C₁-C₂₂ alkyl or optionally substituted C₂-C₂₂ alkenyl, withthe proviso that when R_(x) is OH, it is in the beta configuration (andwhen R_(x) is R_(d), with R_(d) being C(O)R_(e), then it is preferablyin the beta configuration); R₄ is independently selected from H andunsubstituted C₁-C₄ alkyl; R₅ is substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl; R₆is H, optionally substituted C₁-C₄ alkyl, or optionally substitutedC₁-C₄ alkoxy; R₇ is H, optionally substituted C₁-C₄ alkoxy, or anoptionally substituted morpholinyl ring; R₈, when present, is H oroptionally substituted C₁-C₄ alkyl; - - - denotes an optional,additional C—C bond, resulting in either a C═C bond between C₄-C₅ orC₅-C₆, with the proviso that when present, the C₅—H substituent is notpresent; and, - - - denotes an optional, additional C—C bond, resultingin a C═C bond between C₁₆-C₁₇, with the proviso that when present, theR₁ is not ═O, provided that the compound does not have one of thefollowing structures:

or alternatively provided that: (i) when R_(x) is ═O, a C═C bond ispresent between C₄-C₅, and R₅ is CH₂OCH₃, then R₁ is selected frommethoxy, spirooxirane, cyano, nitro, and CH₃C(O)—; and/or (ii) whenR_(x) is beta-OH, a C═C bond is present between C₅-C₆, and R₅ isCH₂OCH₃, then R₁ is selected from methoxy, spirooxirane, cyano, nitro,and HOCH₂C(O)—.
 26. The compound of claim 25, wherein R_(x) is OH in thebeta configuration.
 27. The compound of claim 25, wherein R_(x) is ═O.28. The compound of one of preceding claims 25-27, wherein R₇ isselected from the group consisting of H, methoxy, ethoxy, and anoptionally substituted morpholinyl ring.
 29. The compound of one ofpreceding claims 25-28, wherein R₇ is in the beta position.
 30. Thecompound of one of preceding claims 25-29, wherein R₅ is substitutedmethyl.
 31. The compound of one of preceding claims 25-30, wherein theC₅—H is in the alpha configuration and R₅ is in the beta configuration.32. The compound of one of preceding claims 25-30, wherein the C₅—H isin the beta configuration and R₅ is in the beta configuration.
 33. Thecompound of one of preceding claims 25-32, wherein R₆ is H.
 34. Thecompound of one of preceding claims 25-33, wherein R₂ is ═O, methoxy orH.
 35. The compound of one of preceding claims 25-34, wherein R₄ ismethyl.
 36. The compound of claim 25, wherein a carbon-carbon doublebond is present between the C₄ and C₅ carbon atoms.
 37. The compound ofclaim 25, wherein a carbon-carbon double bond is present between the C₅and C₆ carbon atoms.
 38. The compound of claim 25 having the structure:

or a pharmaceutically acceptable salt thereof, wherein R_(b) isoptionally substituted C₁-C₄ alkyl.
 39. The compound of claim 38 whereinR_(b) is methyl.
 40. The compound of claim 38 or 39, wherein R₁ isbeta-methoxy.
 41. The compound of claim 38 or 39, wherein R₁ isbeta-spirooxirane.
 42. The compound of claim 38 or 39, wherein R₁ isbeta-cyano.
 43. The compound of claim 38 or 39, wherein R₁ is ═O. 44.The compound of claim 38 or 39, wherein R₁ is beta-nitro.
 45. Thecompound of claim 38 or 39, wherein R₁ is beta-CH₃C(O)—.
 46. Thecompound of claim 38 or 39, wherein R₁ is beta-HOCH₂C(O)—.
 47. Thecompound of claim 25, selected from the group consisting of:

and pharmaceutically acceptable salts thereof, wherein R_(b) isoptionally substituted C₁-C₄ alkyl.
 48. The compound of claim 47,wherein R_(b) is methyl.
 49. A pharmaceutically acceptable salt of acompound of one of preceding claims 25-48.
 50. A pharmaceuticalcomposition comprising a compound of one of claims 1-48, apharmaceutically acceptable salt thereof, or a combination of two ormore thereof, and a pharmaceutically acceptable carrier.
 51. A method ofinducing anesthesia in a subject in need thereof, said method comprisingadministering to the subject a therapeutically effective amount of acompound of one of claims 1-48, a pharmaceutically acceptable saltthereof, or a pharmaceutical composition of claim
 50. 52. A method fortreating disorders related to GABA function in a subject in needthereof, said method comprising administering to the subject atherapeutically effective amount of a compound of one of claims 1-48, apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of claim
 50. 53. The method of claim 52, wherein thedisorder is selected from the group consisting of insomnia, mooddisorders, convulsive disorders, anxiety, or symptoms of ethanolwithdrawal.